Uitgangsvraag

Dient profylaxe met N-acetylcysteine (NAC) te worden aanbevolen naast hydratie om de kans om PC-AKI te verkleinen bij patiënten met een normale nierfunctie of met een chronische nierziekte die intravasculair CM krijgen toegediend?

Aanbeveling

Geef geen NAC ter preventie van PC-AKI aan patiënten met een normale of verminderde (eGFR <60 ml/min/1,73m2) nierfunctie.

Inleiding

The mechanism of PC-AKI is not completely understood. Direct cell damage by the iodine-containing contrast medium with subsequent oxidative stress, endothelial dysfunction and decreased nitric oxide (NO) availability is supposed to play major role. Intrarenal NO is crucial for maintaining perfusion and oxygen supply in the renal medulla. NO depletion causes vasoconstriction with hypoperfusion of the renal medulla and local hypoxia. In addition, NO depletion affects tubular fluid composition, tubule-glomerular feed-back signalling and decreases glomerular filtration rate (Liu, 2014).

 

However, some experts have questioned whether acute kidney injury occurring after intravascular administration of iodine-containing CM is not caused by co-existing risk factors and only coincidentally related to the CM especially if contrast media are administered by the intravenous route. In a meta-analysis of controlled studies the incidence of acute kidney injury was similar between patients receiving IV contrast and patients receiving an imaging procedure without contrast media (McDonald, 2013).

 

In addition, it is also difficult to distinguish the effects of contrast media from the effects of physiologic confounders that could either elevate or reduce serum creatinine in patients undergoing radiologic studies (Hofmann, 2004; Krasuski, 2003).

 

There is also a possibility that the effectiveness of NAC could vary by type of iodine-containing contrast medium used, LOCM vs IOCM.

 

A recent analysis did not demonstrate a clear benefit of NAC for patients receiving IV contrast media (Subramaniam, 2016). The same analysis found no association between the effect of NAC on the incidence of PC-AKI and mean baseline serum creatinine levels.

 

The argument for NAC in the decision making process has always been the low risk, the low costs and general availability of the NAC intervention. However, the low costs of NAC itself is offset by extra handling time and a more complex AKI preventive protocol, which are also confounding factors.

 

Thus, it is unclear whether NAC-administration should be recommended to prevent PC-AKI.

Conclusies

Low

GRADE

There is evidence of low quality that N-acetylcysteine does not reduce the risk of PC-AKI in patients with normal kidney function undergoing computer tomography with intravascular iodine-containing contrast administration when compared to placebo.

 

(Hsu, 2012)

 

Low

GRADE

There is evidence of low quality that N-acetylcysteine does not reduce the risk of PC-AKI in patients with impaired kidney function undergoing computed tomography with intravascular iodine-containing contrast administration when compared to placebo.

 

(Kama, 2014; 2006; Kitzler, 2012; Poletti, 2007; Poletti, 2013; Tepel, 2000)

 

Low

GRADE

There is evidence of low quality that N-acetylcysteine does not reduce the risk of PC-AKI in patients with normal kidney function undergoing coronary angiography with intravascular iodine-containing contrast administration when compared to placebo.

 

(Berwanger, 2013; Carbonell 2007; Jaffrey, 2015; Kim, 2010; Kinbara, 2010; Lawlor, 2007; Sadat, 2011; Sandhu, 2006; Tanaka, 2011; Thiele 2010)

 

Low

GRADE

There is evidence of low quality that N-acetylcysteine does not reduce the risk of PC-AKI in patients with decreased kidney function undergoing coronary angiography with intravascular iodine-containing contrast administration when compared to placebo.

 

(ACT, 2011; Castini, 2010; Ferrario, 2009; Gulel, 2005; Habib, 2016, Izani Wan, 2008; Koc, 2012; Kotlyar, 2005; Sadenini, 2017; Seyon, 2007)

 

 

No studies were found that compared oral to intravenous N-acetylcysteine route of administration in patients undergoing intravascular iodine-containing contrast administration.

Samenvatting literatuur

Description of studies

 

CT scan, normal kidney function

One RCT (Hsu, 2012) reported on effects of NAC plus saline hydration (n=106) versus saline hydration only (n=103) in terms of incidence of PC-AKI in patients undergoing CT-scans with intravascular contrast medium. NAC was administered intravenously (600mg) prior to the CT-scan.

 

CT scan, decreased kidney function

A total of 5 RCTs (Kama, 2014; Kitzler, 2012; Poletti, 2007; Poletti, 2013; Tepel, 2000) with 386 patients was included. Three studies described emergency patients (Kama, 2014; Poletti, 2007; Poletti, 2013) while two studies described elective patients (Kitzler, 2012; Tepel, 2000). In two RCTs the N-acetylcysteine was administered orally (Kitzler, 2014; Tepel, 2000), with the total doses varying between 2.4g and 4.8g. In three RCTs the N-acetylcysteine was administered intravenously (Kama, 2014; Poletti, 2007; Poletti, 2013) with total doses varying between 1.05 g (150mg/kg) and 6g. The follow-up time in the studies varied between 3 days and 10 days (for laboratory parameters).

 

Coronary angiography and/or percutaneous intervention, normal kidney function

A total of 8 RCTs was included (Carbonell, 2007; Jaffrey, 2012; Kim, 2010; Kinbara, 2010; Lawlor, 2007; Sadat, 2011; Tanaka, 2011; Thiele, 2010) with 3093 patients was included. Four studies described emergency patients (Carbonell, 2007; Jaffrey, 2012; Tanaka, 2011; Thiele, 2010) while four studies described elective patients (Kim, 2010; Kinbara, 2010; Lawlor, 2007; Sadat, 2011). In four RCTs the N-acetylcysteine was administered orally (Kim, 2010; Kinbara, 2010; Sadat, 2011; Tanaka, 2011), with the total doses varying between 2.4g and 2.8g. In four RCTs the N-acetylcysteine was administered intravenously (Carbonell, 2007; Jaffrey, 2012; Lawlor, 2007; Thiele, 2010) with total doses varying between 1g and 6g. The follow-up time in the studies varied between 2 days and 7 days (for laboratory parameters).

 

Coronary angiography and/or percutaneous intervention, impaired kidney function

A total of 10 RCTs was included (ACT, 2011; Castini, 2010; Ferrario, 2009; Gulel, 2005; Habib, 2016; Izani Wan, 2008; Koc, 2012; Kotlyar, 2005; Sadineni, 2017; Seyon, 2007) with 1188 patients was included. One study described emergency patients (Seyon, 2007) while 7 studies described elective patients (ACT, 2011; Castini, 2010; Ferrario, 2009; Gulel, 2005; Izani Wan, 2008; Koc, 2012; Kotlyar, 2005). In 6 RCTs the N-acetylcysteine was administered orally (ACT, 2011; Castini, 2010; Ferrario, 2009; Gulel, 2005; Izani Wan, 2008; Seyon, 2007), with the total doses varying between 2.4g and 4.8g. In 2 RCTs the N-acetylcysteine was administered intravenously (Koc, 2012; Kotlyar, 2005) with total doses varying between 0.6g and 2.4g. The follow-up time (for laboratory parameters) in the studies varied between 2 days and 30 days.

 

Results

CT scans, normal kidney function

Hsu (2012) reported that 8/106 patients in the NAC group versus 15/103 patients in the control group developed PC-AKI; this difference was not significant: Relative Risk (RR): 0.12 (95% CI: 0.01 to 2.11).

 

CT scans, impaired kidney function

Pooling of data of 5 RCTs (Kama, 2014; 2006; Kitzler, 2012; Poletti, 2007; Poletti, 2013; Tepel, 2000) with 386 patients with 60 events showed that risk ratio of PC-AKI was not reduced significantly in the NAC group: RR: 0.64 (95% CI: 0.24 to 1.70), p=0.37, see Figure 1.

 

Coronary angiography, normal kidney function

Pooling of data of 8 RCTs (Carbonell, 2007; Jaffrey, 2012; Kim, 2010; Kinbara, 2010; Lawlor, 2007; Sadat, 2011; Tanaka, 2011; Thiele, 2010) with 3093 patients with 394 events showed that risk ratio of PC-AKI was not reduced in the NAC group: RR: 0.97 (0.74 to 1.28); p=0.82, see Figure 2.

 

Coronary angiography, impaired kidney function

Pooling of data of 8 RCTs (ACT, 2011; Castini, 2010; Ferrario, 2009; Gulel, 2005; Habib, 2016; Izani Wan, 2008; Koc, 2012; Kotlyar, 2005; Sadineni, 2017; Seyon, 2007) with 1388 patients with 146 events showed that risk ratio of PC-AKI was not reduced in the NAC group: RR: 0.71 (0.51 to 0.98); p=0.16, see Figure 3.

 

Quality of evidence

The quality of evidence for the outcome PC-AKI was downgraded by two for imprecision (low number of events and overlap with 10% border of clinical significance) for all analyses.

 

Figure 1 Meta-analysis of NAC vs Placebo in CT with intravenous CM administration in patients with eGFR <60 ml/min/1.73m2.

F1


Figure 2 Meta-analysis of NAC vs Placebo in Coronary angiography with intra-arterial CM administration in patients with normal kidney function

F2 
Figure 3 Meta-analysis of NAC vs Placebo in Coronary angiography with intra-arterial CM administration in patients with eGFR <60 ml/min/1.73m2.

F3

Zoeken en selecteren

To answer our clinical question a systematic literature analysis was performed for the following research question:

Can prophylactic N-acetylcysteine in addition to hydration reduce the incidence of CI-AKI in patients receiving intravascular contrast?

 

Sub question:

Can prophylactic N-acetylcysteine in addition to hydration reduce the incidence of CI-AKI in patients receiving intravascular contrast in certain subgroups of patient (For example, patients with reduced kidney function)?

 

P (patient category) adult patients undergoing radiological examinations receiving intravascular contrast;

I (intervention) N-acetylcysteine acid in combination with hydration, N-acetylcysteine alone;

C (comparison) hydration alone, no preventive measures;

O (outcome) post-contrast acute kidney injury (PC-AKI), start dialysis, decrease in residual kidney function, adverse effects of hydration (congestion, intensive care unit admittance, and mortality), cost-effectiveness.

 

Relevant outcome measures

The working group considered PC-AKI, mortality and start dialysis critical outcome measures for the decision making process and the intensive care admission important outcome measures for the decision-making process.

 

A difference of at least 10% in relative risk was defined as a clinically relevant difference; by expert opinion of the working group (no literature was available to substantiate the decision). To illustrate, if PC-AKI occurs with an incidence of 10% in the patient population, a difference of 10% of relative risk would mean a difference of 1% in absolute risk. Thus the number needed to treat would be 100, ergo: a doctor would need to treat 100 patients to prevent one case of PC-AKI. When the incidence of PC-AKI is 5%, a difference of 10% in relative risk would mean a difference of 0.5% in absolute risk, and a number needed to treat of 200.

 

Search and select (method)

The databases Medline (OVID), Embase and the Cochrane Library were searched from January 2005 to 23rd of July 2015 using relevant search terms for systematic reviews (SRs) and randomized controlled trials (RCTs). This search was updated on 1 May 2017.

 

A total of 341 studies were found. The initial literature search produced 302 hits and the update produced 39 hits. The following search criteria were applied:

  • adult patients who underwent radiological examination using intravascular iodine-containing contrast media (including radiological examination during percutaneous angiography);
  • patients with impaired kidney function, at least eGFR <60 ml/min1.73m2 were analysed separately from those with a normal kidney function
  • hydration types: hydration with NaCl, hydration with bicarbonate, oral hydration, pre-hydration, pre- and posthydration;
  • N-acetylcysteine that was administered in one of the treatment arms;
  • the control arm consisted of patients that received hydration or no hydration;
  • at least one of the outcome measures was described: Contrast-induced nephropathy (CIN) / contrast-induced acute kidney injury (CI-AKI), start dialysis, decrease in residual kidney function, adverse effects of hydration (overfilling, intensive care unit admittance, and mortality), and cost-effectiveness.

 

Based on title and abstract a total of 91 studies were selected. After examination of full texts a total of 67 studies were excluded and 24 studies definitely included in the literature summary. Reasons for exclusion are described in the exclusion table. During the search update, no more papers were included that described patients with a normal kidney function (eGFR≥60 ml/min1.73m2). The reason for this was that the working group decided to focus the recommendations on patients with an impaired eGFR (<60 ml/min1.73m2) only, because in regular clinical practice no one will consider inserting the administration of NAC in the study protocol in the population with a normal kidney function (eGFR≥60 ml/min1.73m2).

 

Results

24 studies were included in the literature analysis, the most important study characteristics and results were included in the evidence tables. The evidence tables and assessment of individual study quality are included under the tab Onderbouwing.

Referenties

  1. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography main results from the randomized Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT). Circulation 2011;124(11):1250-1259.
  2. Berwanger O, Cavalcanti AB, Sousa AM, et al. Acetylcysteine for the Prevention of Renal Outcomes in Patients With Diabetes Mellitus Undergoing Coronary and Peripheral Vascular Angiography Circ Cardiovasc Interv. 2013;(2), 139-145.
  3. Carbonell N, Blasco M, Sanjuán R, et al. Intravenous N-acetylcysteine for preventing contrast-induced nephropathy: a randomised trial. Int J Cardiol. 2007;115(1):57-62.
  4. Castini D, Lucreziotti S, Bosotti L, et al. Prevention of Contrast-induced Nephropathy: A Single Center Randomized Study. Clin Cardiol. 2010;33(3):E63-8.
  5. Ferrario F, Barone MT, Landoni G, et al. Acetylcysteine and non-ionic isosmolar contrast-induced nephropathy—a randomized controlled study. Nephrol Dial Transplant. 2009;24(10):3103-7.
  6. Gulel O, Keles T, Eraslan H, et al. Prophylactic acetylcysteine usage for prevention of contrast nephropathy after coronary angiography. J Cardiovasc Pharm. 2005;46(4):464-7.
  7. Habib M, Hillis A, Hammad A. N-acetylcysteine and/or ascorbic acid versus placebo to prevent contrast-induced nephropathy in patients undergoing elective cardiac catheterization: The NAPCIN trial; A single-center, prospective, randomized trial. Saudi J Kidney Dis Transpl 2016;27:55-61
  8. Hoffmann U, Fischereder M, Krüger B, et al. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol. 2004;15(2):407-10.
  9. Hsu TF, Huang MK, Yu SH, et al. N-acetylcysteine for the prevention of contrast-induced nephropathy in the emergency department. Intern Med. 2012;51(19):2709-14.
  10. Izani Wan MWM, Zainel D, Zurkurnai Y. Oral N-Acetylcysteine in prevention of contrast induced nephropathy following coronary angiogram. Interl Med Internat Med J. 2008;15(5): 353-361.
  11. Jaffery Z, Verma A, White CJ, et al. A randomized trial of intravenous N-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes. Cathetern Cardiovasc Intervent. 2012;79(6):921-6.
  12. Kama A, Yilmaz S, Yaka E, et al. Comparison of Short-term Infusion Regimens of N-Acetylcysteine Plus Intravenous Fluids, Sodium Bicarbonate Plus Intravenous Fluids, and Intravenous Fluids Alone for Prevention of Contrast-induced Nephropathy in the Emergency Department. Acad Emerg Med. 2014;21(6):615-22.
  13. Kim BJ, Sung KC, Kim BS, et al. Effect of N-acetylcysteine on cystatin C-based renal function after elective coronary angiography (ENABLE Study): a prospective, randomized trial. Int J Cardiol. 2010;138(3):239-45.
  14. Kinbara T, Hayano T, Ohtani N, et al. Efficacy of N-acetylcysteine and aminophylline in preventing contrast-induced nephropathy. J Cardiol. 2010;55(2):174-9.
  15. Kitzler TM, Jaberi A, Sendlhofer G, et al. Efficacy of vitamin E and N-acetylcysteine in the prevention of contrast induced kidney injury in patients with chronic kidney disease: a double blind, randomized controlled trial. Wiener Klin Wochenschr. 2012;124(9-10):312-9.
  16. Koc F, Ozdemir K, Kaya MG, et al. Intravenous N-acetylcysteine plus high-dose hydration versus high-dose hydration and standard hydration for the prevention of contrast-induced nephropathy: CASIS—a multicenter prospective controlled trial. Int J Cardiol. 2012;155(3):418-23.
  17. Kotlyar E, Keogh AM, Thavapalachandran S, et al. Prehydration alone is sufficient to prevent contrast-induced nephropathy after day-only angiography procedures—a randomised controlled trial. Heart Lung Circ. 2005;14(4):245-51.
  18. Krasuski RA, Beard BM, Geoghagan JD, et al. Optimal timing of hydration to erase contrast-associated nephropathy: the OTHER CAN study. J Invas Cardiol. 2003;15(12):699-702.
  19. Lawlor DK, Moist L, DeRose G, et al.. Prevention of contrast-induced nephropathy in vascular surgery patients. Ann Vasc Surg. 2007 Sep;21(5):593-7.
  20. Liu ZZ, Schmerbach K, Lu Y, et al. Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedbackAm J Physiol Renal Physiol. 2014;306(8):F864-72.
  21. McDonald JS, McDonald RJ, Carter RE, et al. Risk of intravenous contrast material–mediated acute kidney injury: a propensity score–matched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014;271(1):65-73.
  22. O'Sullivan S, Healy DA, Moloney MC, et al. The role of N--acetylcysteine in the prevention of contrast-induced nephropathy in patients undergoing peripheral angiography a structured review and meta-analysis. Angiology. 2013;64(8):576-82.
  23. Poletti PA, Platon A, De Seigneux S, et al. N-acetylcysteine does not prevent contrast nephropathy in patients with renal impairment undergoing emergency CT: a randomized study. BMC Nephrol. 2013;14:119.
  24. Poletti PA, Saudan P, Platon A, et al. Iv N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. AJR Am J Roentgenol. 2007;189(3):687-92.
  25. Sadat U, Walsh SR, Norden AG, et al. Does oral N-acetylcysteine reduce contrast-induced renal injury in patients with peripheral arterial disease undergoing peripheral angiography? A randomized-controlled study. Angiology. 2011;62(3):225-30.
  26. Sadineni R, Karthik K, Swarnalatha G, et al. N-acetyl cysteine versus allopurinol in the prevention of contrast nephropathy in patients with chronic kidney disease: A randomized controlled trial. Indian J Nephrol. 2017 Mar-Apr; 27(2): 93–98.
  27. Sandhu C, Belli AM, Oliveira DB. The role of N-acetylcysteine in the prevention of contrast-induced nephrotoxicity. Cardiovasc Intervent Radiol. 2006;29(3), 344-347.
  28. Seyon RA, Jensen LA, Ferguson IA, et al. Efficacy of N-acetylcysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention. Heart Lung. 2007;36(3):195-204.
  29. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016;164(6):406-16.
  30. Sun Z, Fu Q, Cao L, et al. Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. PloS One 8.1. 2013;8(1):e55124.
  31. Tanaka A, Suzuki Y, Suzuki N, et al. Does N-acetylcysteine reduce the incidence of contrast-induced nephropathy and clinical events in patients undergoing primary angioplasty for acute myocardial infarction? Intern Med.. 2011;50(7):673-7.
  32. Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343(3):180-4.
  33. Thiele H, Hildebrand L, Schirdewahn C, et al. Impact of high-dose N-acetylcysteine versus placebo on contrast-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: the LIPSIA-N-ACC (Prospective, Single-Blind, Placebo-Controlled, Randomized Leipzig Immediate PercutaneouS Coronary Intervention Acute Myocardial Infarction N-ACC) Trial. J Am Coll Cardiol. 2010;55(20):2201-9.

Evidence tabellen

Table: Exclusion after revision of full text

Author and year

Reason for exclusion

ACT Investigators, 2009

description of study design, not an original article

Amini, 2009

Prehydration only, not comparable to Dutch clinical practice

Ashworth, 2010

overlaps with Loomba, 2013 and is a less recent review

Azmus, 2005

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Bagshaw, 2006

review, not systematic

Berwanger, 2012

Sub-analysis of ACTT studty (which is already included in literature analysis)

Briguori, 2011

Does not compare N-acetylcysteine to placebo

Briguori, 2007

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Brown, 2009

overlaps with Loomba, 2013 and is a less recent review

Burns, 2010

Not specifically patients with normal or abnormal kieny function (mix of impaired kidney function and diabetics)

Busch, 2013

overlaps with Loomba, 2013 and is a less recent review

Buyukhatipoglu, 2010

outcome measures as described in PICO not reported

Calabro, 2011

observational study

Carbonell, 2010

already included in Loomba 2013, and Sun, 2013

Carbonell, 2007

already included in Loomba 2013, and Sun, 2013

Chen, 2008

does not compare no NAC to NAC (both treatment arms recieve NAC)

Coyle, 2006

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Duong, 2005

overlaps with Loomba, 2013 and is a less recent review

Gomes, 2005

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Gonzales, 2007

overlaps with Loomba, 2013 and is a less recent review

Gouveira, 2015

review, not systematic

Gulel, 2005

already included in Loomba 2013

Gurm, 2011

Does not answer study question

Hafiz, 2012

Acetylcysteine not compared to control

Hassan, 2011

observational study

Housseinjani, 2013

review, not systematic

Hsu, 2012

already included in review Wu 2013

Hsu, 2007

already included in review Wu 2013

Izcovich, 2015

systematic review, poor quality (no clear description of included studies)

Jo, 2009

does not compare no NAC to NAC

Juergens, 2010

does not compare no NAC to NAC (both treatment arms recieve NAC)

Khalili, 2006

Prehydration only, not comparable to Dutch clinical practice

Kim, 2010

already included in Loomba 2013

Kotlyar, 2005

Dubbel met Kotlyar, 2005

Lee, 2011

does not compare no NAC to NAC (both treatment arms recieve NAC)

Liu, 2006

overlaps with Loomba, 2013 and is a less recent review

Marenzi, 2006

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Mittal, 2014

review, not systematic

Momeni, 2012

Observational study

O’Sullivan 2013

Does not answer reseach question broadly enough, used for cross refernecing

Ratcliffe, 2009

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Ritz, 2006

letter to the editor, not an original article

Sandhu, 2006

Unclear if patients were hydrated next to the NAC administration or not

Sar, 2010

Not specifically patients with normal or abnormal kidney function (mix of impaired kidney function and diabetics)

Shabbir, 2015

Article not found

Shalansky, 2006

review, not systematic

Solomon, 2014

review, not systematic

Staniloae, 2009

subanalysis of trial, observational data

Thiele, 2010

already included in Loomba 2013

Trivedi, 2009

overlaps with Loomba, 2013 and is a less recent review

Zagler, 2006

overlaps with Loomba, 2013 and is a less recent review

 

Risk of bias table for intervention studies (randomized controlled trials)

Research question:

Study reference

 

 

 

(first author, publication year)

Describe method of randomisation1

Bias due to inadequate concealment of allocation?2

 

 

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?3

 

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?3

 

 

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?3

 

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?4

 

 

 

(unlikely/likely/unclear)

Bias due to loss to follow-up?5

 

 

 

 

 

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?6

 

 

 

(unlikely/likely/unclear)

CT scan, normal kidney function

Hsu, 2012

Computer-generated random numbers

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

CT scan, decreased kidney function

Kama, 2014

By website randomization.com

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Kitzler, 2012

Not reported

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Unclear

Poletti, 2007

Randomized by serial enrolment

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Poletti, 2013

Computer generated randomization list

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unlikely

Tepel, 2000

“Randomly assigned”

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unlikely

CAG or PCI, normal kidney function

Carbonell, 2007

Computer-generated random numbers

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Jaffery, 2012

“Randomly assigned”

Unlikely

Unlikely

Unlikely

Unlikely

Likely

Unlikely

Unclear

Kim, 2010

Computer-generated random numbers

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Kinbara, 2010

“Randomly assigned”

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Lawlor, 2004

“randomization was performed by the hospital clinical trials pharmacist”

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Sadat, 2011

Computer generated randomization scheme

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Tanaka, 2011

“Randomly assigned”

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Thiele, 2010

Computer generated random numbers

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

CAG or PCI, decreased kidney function

ACT, 2011

24-hour Web-based automated randomization system

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Castini, 2010

Computer generated randomization table

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Ferrario, 2009

Computer generated randomization list

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Gulel, 2005

Random allocation table

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Habib, 2016

Patients were randomized into three groups

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Izani Wan (Mohamed), 2008

Computer generated randomization list

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Koc, 2012

Not described

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Kotlyar, 2005

Not described

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Sadineni, 2017

Patients were randomly assigned

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

Seyon, 2007

Not described

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely

Unclear

Unclear

  1. Randomisation: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
  2. Allocation concealment: refers to the protection (blinding) of the randomisation process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomisation (performed at a site remote from trial location) or sequentially numbered, sealed, opaque envelopes. Inadequate procedures are all procedures based on inadequate randomisation procedures or open allocation schedules..
  3. Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments. The outcome assessor records the study results. Blinding of those assessing outcomes prevents that the knowledge of patient assignement influences the proces of outcome assessment (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
  4. Results of all predefined outcome measures should be reported; if the protocol is available, then outcomes in the protocol and published report can be compared; if not, then outcomes listed in the methods section of an article can be compared with those whose results are reported.
  5. If the percentage of patients lost to follow-up is large, or differs between treatment groups, or the reasons for loss to follow-up differ between treatment groups, bias is likely. If the number of patients lost to follow-up, or the reasons why, are not reported, the risk of bias is unclear
  6. Participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the risk of bias is unclear; an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.

 

Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies [cohort studies, case-control studies, case series])1

This table is also suitable for diagnostic studies (screening studies) that compare the effectiveness of two or more tests. This only applies if the test is included as part of a test-and-treat strategy – otherwise the evidence table for studies of diagnostic test accuracy should be used.

 

Research question:

Study reference

Study characteristics

Patient characteristics 2

Intervention (I)

Comparison / control (C) 3

 

Follow-up

Outcome measures and effect size 4

Comments

CT scan, normal kidney function

Hsu, 2012

Type of study: Randomized controlled trial

 

Setting: emergency department, medical teaching center

 

Country: Taiwan

 

Source of funding: non-commercial

Inclusion criteria:

1) all adult patients who received chest or abdominal contrast-enchanced computed tomography (CECT)

 

Exclusion criteria:

1) patients undergoing long-term hemodialysis or peritoneal hemodialysis

2) patients who received another dose of contrast medium within 72 hours

3) patient refused to sign concent forms

4) patients had a knon allergic reaction to N-acetlycysteine (NAC)

 

N total at baseline:

Intervention: 106

Control: 103

 

Important prognostic factors2:

For example

age ± SD:

I: 80 ± 9

C: 80 ± 11

 

Sex:

I: 74% M

C: 76% M

Baseline SCr (mg/dL) ± SD

I: 1.40 ± 0.58

C: 1.26 ± 0.43

 

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

 

600mg NAC

In 0.9% sodium chloride (3 mL/kg/h) for 60 minutes prior to the CECT

 

0.9% sodium chloride (1 mL/kg/h) for 6 hours after CECT

 

 

 

Describe control (treatment/procedure/test):

 

0.9% sodium chloride (3 mL/kg/h) for 60 minutes prior to the CECT

 

0.9% sodium chloride (1 mL/kg/h) for 6 hours after CECT

 

 

Length of follow-up:

72 hours

 

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN05:

(=a rise in SCr ≥0.5mg/dL within 48-72 hours after CECT imaging)

I: 7.5%

C: 14.6%

Odds Ratio (OR): 0.31 (95% CI: 0.10 – 0.96, p=0.04)

 

CINor:

(=a rise in SCr ≥0.5mg/dL or 25% within 48-72 hours after CECT imaging)

I: 11.3%

C: 19.4%

OR: 0.35 (95% CI: 0.13 – 0.91, 0=0.03)

 

Mortality:

I: 7.5%

C: 12.6%

OR: 0.49 (95% CI: 0.15 – 1.55, p=0.22)

 

Permanent renal replacement therapy:

0% in both groups

Authors’ conclusion:

A singe dose of NAC before CECT imagingcan prevent CIN in an ED setting. However it does not improve mortality rate or the need for dialysis.

 

Patients with congestive pulmonary edema received an adjusted hydration schedule where the rates of fluid loading were decreased by 50%.

CT scan, decreased kidney function

Kama, 2014

Type of study: randomized controlled trial

 

Setting: emergency department, academic tertiary hospital

 

Country: Turkey

 

Source of funding: not reported

Inclusion criteria:

1) adult patients (≥18 years) who presented to the emergency department

2) patients who received CECT as part of their emergency care

3) moderate or high risk for contrast induced nephropathy (CIN) according to Mehran score (>5)

 

Exclusion criteria:

1) CIN risk determine as Low by Mehran score

2) history of contrast-related allergies

3) hemodynamically unstable patients requiring resuscitation or surgery

4) patients receiving renal replacement therapy

5) patients did not provide infomed consent

 

N total at baseline:

Intervention: 36

Control: 35

 

Important prognostic factors2:

For example

age (95% CI):

I: 69 (65-73)

C: 67 (62-72)

 

Sex:

I:69 % M

C: 65% M

 

eGFR <20 mL/min/1.73m2

I: 25%

C: 9%

eGFR 40-20 mL/min/1.73m2

I: 36%

C: 46%

eGFR 60-40mL/min/1.73m2

I: 11%

C: 14%

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

150mg/kg NAC

In 1000mL in 0.9% saline at the rate of 350ml/hour for 3 hours

Before, after and during administration of contrast

 

 

Describe control (treatment/procedure/test):

 

1000mL 0.9% saline at the rate of 350ml/hour for 3 hours

Before, after and during administration of contrast

 

Length of follow-up:

48-72 hours

Patients who were diagnosed with CIN – 1 months

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=25% increase or greater than 0.5mg/dL (44µmol/L) increase in the serum creatinine level, 48-72 hours after administration of the contrast agent compared with the baseline creatinine measurement)

I: 7 (19%)

C: 5 (14%)

p>0.05

 

No contrast- or treatment-induced adverse events were detected during emergency department care

Authors’conclusion:

None of the short-term protocols with normal saline or NAC was superior in the emergency department pateints requiring CECT who had a moderate or high risk of CIN.

Kitzler, 2012

Type of study: randomized controlled trial

 

Setting: single-center, elective patients

 

Country:

 

Source of funding:

Inclusion criteria:

-patients with chronic kidney disease stage 1-4 undergoing elective computer-assisted tomography with non-ionic radiocontrast agents when compared to 0.45% saline alone

 

Exclusion criteria:

-

 

N total at baseline:

Intervention: 10

Control: 10

 

Important prognostic factors2:

For example

age ± SD: mean: 75 years (not reported per group)

 

Sex:

38% M

(not reported per group)

 

Groups comparable at baseline? Unc;ear

Describe intervention (treatment/procedure/test):

 

N-acetylcysteine

4800mg per os

 

0.45% saline, 1mL/kg/h over 24 hours

 

 

Describe control (treatment/procedure/test):

 

0.45% saline, 1mL/kg/h over 24 hours

 

Length of follow-up:

Not reported

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

No patients developed contrast induced acute kidney injury.

 

There was no significant difference in serum creatinine change between the three study arms.

Authors’ conclusion:

Following radiocontrast administration neither vitamin E nor NAC in addition to saline demonstrated an additional beneficial effect on kidney fi=unction when compared to saline alone.

Poletti, 2007

Type of study: randomized controlled trial

 

Setting: emergency patients

 

Country: Switzerland

 

Source of funding: not reported

Inclusion criteria:

1) patients admitted consecutively to the emergency department during daytime hours

2) serum creatinine >1.2md/dL

 

Exclusion criteria:

1) pregnancy

2) end stage renal failure with dialysis

3) suspicion of acute renal obstruction

4) asthma

5) severe cardiac failure

6) hemodynamically unstable condition contraindicating iv hydration

7) nonurgent indications for CT

 

N total at baseline: 87

Intervention: 44

Control: 43

 

Important prognostic factors2:

For example

age ± SD:

I: 70 ± 19

C: 73 ± 17

 

Sex:

I: 59% M

C: 67% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

900mg NAC diluted in 5% glucose solution administered iv 1 hour before CT

 

0.45% saline iv at a rate of 5mL/kg body weight over the course of an hour before CT

 

900mg NAC mixed into the 0.45% saline perfusion administered iv after completion of CT at a rate of 1mL/kg body weight per hour for 12 hours

 

 

 

 

Describe control (treatment/procedure/test):

 

placebo in 5% glucose solution administered iv 1 hour before CT

 

0.45% saline iv at a rate of 5mL/kg body weight over the course of an hour before CT

 

placebo mixed into the 0.45% saline perfusion administered iv after completion of CT at a rate of 1mL/kg body weight per hour for 12 hours

 

 

Length of follow-up:

4 days

 

Loss-to-follow-up:

7 (8%)

3 died, 3 left hospital 1 transferred to another hospital (not reported per group)

 

Incomplete outcome data:

As above

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

Nephrotoxicity

(=≥25% increase in serum creatinine value)

I: 2/44 (5%)

C: 9/43 (21%)

P=0.026

Authors’ conclusion:

 

On the basis of the serum creatinine concentration, iv administration of NAC appears protective against the nephrotoxicity of contrast medium.

Poletti, 2013

Type of study: randomized controlled trial

 

Setting: emergency department patients

 

Country: Switzerland

 

Source of funding: not reported

Inclusion criteria:

1) patients admitted consecutively to the emergency department

2) estimated creatinine clearance by MDRD of <60ml/min/1.73m2

 

Exclusion criteria:

1) asthma

2) pregnancy

3) obstructive nephropathy

4) patient’s refusal

 

N total at baseline: 104

Intervention: 55

Control: 59

 

Important prognostic factors2:

For example

age ± SD:

I: 78 ± 12

C: 78 ± 12

 

Sex:

I: 49% M

C: 51% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

6000mg NAC iv diluted in 100mL saline, administered in the 60 minutes before the CT-scan

 

Hydration of 250mL of 0.45% saline before CT-scan

 

1000mL saline 0.45% after CT-scan

 

 

Describe control (treatment/procedure/test):

 

placebo diluted in 100mL saline, administered in the 60 minutes before the CT-scan

 

Hydration of 250mL of 0.45% saline before CT-scan

 

1000mL saline 0.45% after CT-scan

 

Length of follow-up:

10 days

 

Loss-to-follow-up:

Intervention:

3 (5%)

Reasons not reported

 

Control:

1 (2%)

Reasons not reported

 

Incomplete outcome data:

As above

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Nephropathy

(=increase of at least 25% or 44µmol/l in serum creatinine level at day 2,4 or 10 compared to day 0)

I: 8 (15%)

C: 10 (17%)

P=0.99

 

Composite event of death or acute kidney injury

I: 33%

C: 24%

p-value not reported

Authors’ conclusion:

 

An ultra-high dose of intravenous NAC is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT.

Tepel, 2000

Type of study: Randomized controlled trial

 

Setting: elective patients receiving CT-scan at hospital

 

Country: Germany

 

Source of funding: not reported

Inclusion criteria:

1) patients with a serum creatinine >1.2mg/dL or creatinine clearance <50mL/min

2) known chronic renal failure and a stable serum creatinine concentration

3) patients receiving elective CT-scans

 

Exclusion criteria:

1) acute renal failure

 

N total at baseline:

Intervention: 41

Control: 42

 

Important prognostic factors2:

For example

age ± SD:

I: 66±11

C: 65 ± 15

 

Sex:

I:59 % M

C: 55% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

Acetylcycsteine orally 600mg twice daily on the day before and on the day of administration of the contrast agent

 

Saline (0.45%) iv. 1ml/kg/h for 12 hours before and 12 hours after contrast administration

 

 

 

 

Describe control (treatment/procedure/test):

 

Saline (0.45%) iv. 1ml/kg/h for 12 hours before and 12 hours after contrast administration

 

Length of follow-up:

48 hours, 6 days

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Increase of at least 0.5mg/dL (44µmol/L) in serum creatinine concentration 48 hours after administration of contrast agent:

I: 1/41 (2%)

C: 9/42 (21%)

RR: 0.1 (95% CI: 0.01 – 0.9)

P=0.01

 

None of the patients required dialysis

Authors’ conclusion:

 

Prophylactic administration of the antioxidant acetylcysteine, along with hydration, prevents the reduction in renal function induced by iopromide, a non-ionic, low-osmolality contrast agent, in patients with chronic renal insufficiency.

CAG or PCI, normal kidney function

Carbonell, 2007

Type of study: randomized controlled trial

 

Setting: tertiary hospital, cardiac unit

 

Country: Spain

 

Source of funding: not reported

Inclusion criteria:

1) patients with acute coronary syndrome and normal renal function, admitted to the cardiac unit and referred for cardiac catheterization

2) angina at rest or post-myocardial infarction

Or they had received thrombolytic therapy with failed recanalization so the cardiac catheterisation was an emergency procedure

 

Exclusion criteria:

1) chronic renal failure or acute renal dysfunction

2) hemodynamic instability (systolic blood pressure <90mmHg)

3) known allergy to NAC or contrast agents

4) untreated gastrointestinal bleeding

5) previous treatment with theophylline, mannitol or nephrotoxic antibiotics

 

N total at baseline:

Intervention: 107

Control: 109

 

Important prognostic factors2:

For example

age ± SD:

I: 63 ± 14

C: 61 ± 12

 

Sex:

I: 80% M

C: 73% M

 

Creatinine clearance (ml/min)

I: 86 ± 29

C: 88 ± 30

 

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

 

NAC (600mg diluted in 50mL of 0.9% saline) iv for 30 minutes twice daily for a total of 4 times

Starting at least for 6 hours before the administration of contrast media

 

0.9% saline iv at least 6 hours before procedure, maintained for 12 hours after contrast dosing

 

 

 

 

Describe control (treatment/procedure/test):

 

placebo (diluted in 50mL of 0.9% saline) iv for 30 minutes twice daily for a total of 4 times

Starting at least for 6 hours before the administration of contrast media

 

0.9% saline iv at least 6 hours before procedure, maintained for 12 hours after contrast dosing

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Contrast induced nephropathy

(=an acute increase in the serum creatinine concentration ≥0.5mg/dL and/or >25% increase above baseline level at 48 hours after contrast dosing)

I; 10.3%

C: 10.1%

P=0.50

 

None of the patients required dialysis.

Patients with congestive heart failure received a reduced hydration volume.

 

Authors’ conclusion:

The prophylactic administration of intravenous NAC provides no additional benefit to saline in high-risk coronary patients with normal renal function.

Jaffery, 2012

Type of study: randomized controlled trial

 

Setting: single-center inpatients, emergency procedure

 

Country: United States of America

 

Source of funding: not reported

Inclusion criteria:

1) patients hospitalized with a primary diagnosis of acute coronary syndrome

2) scheduled for coronary angiography (CAG) or intervention during this hospitalization

3) age ≥18 years

 

Exclusion criteria:

1) end stage renal disease requiring dialysis

2) hypersensitivity to NAC

3) history of life-threatening contrast reaction

 

N total at baseline:

Intervention: 192

Control: 206

 

Important prognostic factors2:

For example

age ± SD:

I: 66 ± 13

C: 65 ± 13

 

Sex:

I: 67 % M

C: 59 % M

 

Baseline creatinine clearance (ml/min)

I: 87 ± 41

C: 92 ± 44

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC: 1200mg bolus followed by 200mg/h for 24 hours

 

In 500ml 5% dextrose solution of water iv

 

Normal saline (0.9%) iv; 1/ml/kg for 24 hours

 

Describe control (treatment/procedure/test):

 

 

Placebo in 500ml 5% dextrose solution of water iv

 

Normal saline (0.9%) iv; 1/ml/kg for 24 hours

 

Length of follow-up:

72 hours for lab parameters

30 days for mortality and hospital stay

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=increase in serum creatinine concentration ≥25% above the baseline level within 72 hours of the administration of intravenous contrast)

I: 16%

C:
13%

P=0.40

 

Outcomes of mortality and length of hospital not reported.

Patients with clinical evidence of heart failure received only NAC iv or placebo

 

Authors’ conclusion:

In acute coronary syndrome patients undergoing CAG with or without percutaneous intervention (PCI), high-dose intravenous NAC failed to reduce the incidence of CIN.

Kim, 2010

Type of study: randomized controlled trial

 

Setting: elective patients, one hospital

 

Country: South Korea

 

Source of funding: not reported

Inclusion criteria:

1) patients scheduled for elective CAG and/or PCI with apparently normal renal function

 

Exclusion criteria:

1) acute coronary syndrome requiring emergency CAG/PCI

2) cardiogenic shock

3) iodinated contrast media administration within a monthor NAC within 48 hours before study entry

4) current dialysis or a serum creatinine >1.4mg/dL for men or >1.2mg/dL for women

5) thyroid diseases

6) allergy to the study medication

 

N total at baseline:

Intervention: 80

Control: 86

 

Important prognostic factors2:

For example

age ± SD:

I: 62 ± 11

C: 62 ± 10

 

Sex:

I: 79% M

C: 67% M

 

SCr (mg/dL)

I: 1.03 ± 0.17

C: 1.03 ± 0.14

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

Oral acetylcysteine

600mg twice a day on the day before and the day of coronary angiography

 

0.9% saline 1/mL/kg/h for 12 hours before and 6hours after CAG

 

 

Describe control (treatment/procedure/test):

 

0.9% saline 1/mL/kg/h for 12 hours before and 6hours after CAG

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=increase in sCR of at least 0.5mg/dL or >25% within 48 hours of contrast exposure)

I: 3.8%

C: 8.1%

p>0.05

Authors’ conclusion:

 

Not relevant – based on cystatin-C defined CIN results and not the sCR based CIN.

Kinbara, 2010

Type of study: randomized controlled trial

 

Setting: elective patients, one hospital

 

Country: Japan

 

Source of funding: not reported

Inclusion criteria:

1) Patients with stable coronary artery disease scheduled to undergo CAG and/or PCI, with stable serum creatinine concentrations

 

Exclusion criteria:

1) acute myocardial infarction

2) use of vasopressors before PCI

3) cardiogenic shock

4) current peritoneal or hemodialysis

5) planned post-contrast dialysis

6) allergies to ths study medications

7) congestive heart disease

8) severe valvular disease

9) pregnancy

10) multiple myeloma

11) amyloidosis

 

N total at baseline:

Intervention: 15

Control: 15

 

Important prognostic factors2:

For example

age ± SD:

I: 70 ± 10

C: 70 ± 8

 

Sex:

I: 80% M

C: 80% M

 

SCr (mg/dL)

I: 1.00 ± 0.36

C: 0.94 ± 0.21

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

NAC 704mg orally twice daily on the day before ond on the day of CAG and/or PCI

 

0.9% saline iv 1/ml/kg/hour

For 30 minutes before and 10 hours after angiography

 

 

Describe control (treatment/procedure/test):

 

0.9% saline iv 1/ml/kg/hour

For 30 minutes before and 10 hours after angiography

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=SCr increase of >0.5mg/dL from baseline to 48 hours to angiography)

I: 0 (0%)

C: 4 (27%)

96% CI: 0.10 – 5.991, p=0.011

Authors’ conclusion:

 

These results suggest that both prophylactic NAC and aminophylline administration are effective in preventing CIN, but not with hydration alone.

Lawlor, 2004

Type of study: randomized controlled trial

 

Setting: elective patients, single center

 

Country: United Kingdom

 

Source of funding: not reported

Inclusion criteria:

1) patients with peripheral vascular disease going for elective angiography or angioplasty to participate in this trial

 

Exclusion criteria:

-

 

N total at baseline:

Intervention: 46

Control: 48

 

Important prognostic factors2:

For example

age ± SD:

I: 72 ± 12

C: 69 ± 12

 

Sex:

I: 59% M

C: 69% M

 

SCr (µmol/L)

I: 110 ± 42

C: 124 ± 63

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

1g of NAC in each bag of 0.9% saline

 

0.9% saline (500mL over 4-6 hours) 6-12 hours prior to angiography and again after angiography

Describe control (treatment/procedure/test):

 

 

0.9% saline (500mL over 4-6 hours) 6-12 hours prior to angiography and again after angiography with placebo

Length of follow-up:

7 days

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

 

CIN (=a rise of 25% or 0.5mg/dL in sCR at 48 hours after contrast administration)

 

Patients with normal kidney function:

I: 0/29 (0%)

C: 0/27 (0%)

p>0.05

 

Patients with decreased kidney function:

I: 3/17 (18%)

C: 3/21 (14%)

p>0.05

Authors’ conclusion:

 

NAC pre-contrast and post-contrast does not confer any benefit in preventing radiocontrast induced nephropathy in vascular patients

Sadat, 2011

Type of study: randomized controlled trial

 

Setting: elective patients, single center

 

Country: United Kingdom

 

Source of funding: no funding

Inclusion criteria:

1) patients undergoing peripheral angiography for peripheral artery disease

 

Exclusion criteria:

1) patients with established renal failure – on renal replacement therapy

 

N total at baseline:

Intervention: 21

Control: 19

 

Important prognostic factors2:

For example

age ± SD:

I: 75 ± 11

C: 70 ± 14

 

Sex:

Not reported

 

Groups comparable at baseline? Unclear

Describe intervention (treatment/procedure/test):

 

NAC 600mg twice daily orally on the ay before and on the day of CAG (2.4g in total)

 

Iv hydration 0.9% saline

1L over 12 hours before CAG

1L over 12 hours after CAG

 

 

 

Describe control (treatment/procedure/test):

 

Iv hydration 0.9% saline

1L over 12 hours before CAG

1L over 12 hours after CAG

 

Length of follow-up:

72 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=0.5mg/dL or 25% increase in sCr from baseline value within 48 hours of exposure to intravascular radiographic contrast media that is not attributable to other causes)

I: 1/21 (5%)

C: 3/19 (16%)

P=0.33

Authors’ conclusion:

 

A clear conclusion is not formulated.

Tanaka, 2011

Type of study: randomized controlled trial

 

Setting: emergency patients, single center

 

Country: Japan

 

Source of funding: not reported

Inclusion criteria:

1) patients admitted for ST-segment elevation acute myocardial infarction treated with primary PCI

 

Exclusion criteria:

1) dialysis

2) known allergy to NAC

3) inability to take NAC orally

 

N total at baseline:

Intervention: 38

Control: 38

 

Important prognostic factors2:

For example

age ± SD:

I: 63 ± 13

C: 61 ± 14

 

Sex:

I: 82% M

C: 82% M

 

SCr (mg/dL)

I: 0.95 ± 0.34

C: 0.88 ± 0.25

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 705mg orally before and 12, 24, 26 pours after intervention (2.8g in total)

 

Hydration with iv Ringer lactate solution at a rate of 1-2ml/kg/hour for more than 12 hours after primary CAG

Describe control (treatment/procedure/test):

 

 

Hydration with iv Ringer lactate solution at a rate of 1-2ml/kg/hour for more than 12 hours after primary CAG

Length of follow-up:

36 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=an increase in sCr level of 25% or more from baseline value within 72 hours after primary angioplasty)

I: 2/38 (5%)

C: 5/38 (13%)

P=0.21

 

No major adverse events (death, acute renal failure requiring temporary replacement therapy, need for mechanical ventilation) occurred in either group during the in-hospital follow-up period.

Authors’ conclusion:

 

While N=acetylcysteine might have the possibility to reduce the incidence of contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction, the in-hospital mortality and morbidity were not significantly different between the two groups.

Thiele, 2010

Type of study: randomized controlled trial

 

Setting: emergency patients, one tertiary hospital

 

Country: Germany

 

Source of funding: not reported

Inclusion criteria:

1) patients with acute myocardial infarction undergoing primary PCI

2) symptoms <12 hours and ST-segment elevation ≥0.1mV in ≥2 extremity leads or ≥o.2 mV in ≥2 ore-cordial leads

 

Exclusion criteria:

1) previous fibrinolysis <12 hours

2) known NAC allergy

3) chronic dialysis

4) pregnancy

5) contra-indications for magnetic resonance imaging

 

N total at baseline:

Intervention: 126

Control: 125

 

Important prognostic factors2:

For example

age (interquartile range):

I: 68 (57-75)

C: 68 (56-76)

 

Sex:

I: 71% M

C: 66% M

 

SCr (µmol/L; interquartile range)

I: 81 (69-97)

C: 78 (67-90)

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC intravenous bolus

1200mg before CAG

And 1200mg twice daily for 48 hours

(total dose 6g)

 

Hydration with intravenous 0.9% saline; infusion rate 1ml/kg/hour for 12 hours (or 0.5mg/kg/h in overt heart failure)

 

Describe control (treatment/procedure/test):

 

 

10mL of 0.9% saline at each injection

 

 

 

 

Hydration with intravenous 0.9% saline; infusion rate 1ml/kg/hour for 12 hours (or 0.5mg/kg/h in overt heart failure)

 

Length of follow-up:

Laboratory parameters: 72 hours

Clinical endpoints: 6 months

 

Loss-to-follow-up:

none

 

Incomplete outcome data:

none

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=increase in sCr of ≥25% from baseline within 72 hours after PCI)

I: 18/126 (14%)

C: 25/125 (20%)

P=0.28

 

Mortality after 6 months

I: 12/126 (14%)

C: 12/125 (14%)

p>0.05

 

New congestive heart failure

I: 11/126 (9%)

C: 7/125 (6%)

p>0.05

Authors’ conclusion:

 

High-dose iv NAC does not provide additional clinical benefit to placebo with respect to CIN in non-selected patients undergoing angioplasty with moderate doses of contrast medium and optimal hydration.

CAG or PCI, decreased kidney function

ACT, 2011

Type of study: randomized controlled trial

 

Setting: inpatients, elective, multi-centre

 

Country: Brazil

 

Source of funding: non-commercial

Inclusion criteria:

1) patients undergoing CAG or peripheral arterial angiography

2) at least one risk factor for CI-AKI:

-age >70 years

-chronic renal failure

-diabetes mellitus

-clinical evidence of congestive heart failure

-left ventricular ejection fraction <0.45

-hypotension

 

Exclusion criteria:

-patients on dialysis

-patients with ST-segment elevation myocardial infarction

-pregnancy or breastfeeding

-women <45 years who did not use contraceptive methods

 

N total at baseline:

Intervention: 1172

Control: 1136

 

With eGFR<30 ml/min

I: 68

C: 63

 

With eGFR 30 to 60 ml/min

I: 515

C: 492

 

Important prognostic factors2:

For example

age ± SD:

I: 68 ± 10

C: 68 ± 10

 

Sex:

I: 62% M

C:61 % M

 

Groups comparable at baseline? Yes

 

Describe intervention (treatment/procedure/test):

 

NAC 2x600mg orally every 12 hours for 2 days

(2 doses before and 2 doses after contrast administration, total dose 4800mg)

 

Hydration with 0.9% saline 1mg/kg/hour from 6-12 hours before to 6-12 hours after angiography

 

 

Describe control (treatment/procedure/test):

 

 

placebo orally every 12 hours for 2 days

(2 doses before and 2 doses after contrast administration)

 

 

 

Hydration with 0.9% saline 1mg/kg/hour from 6-12 hours before to 6-12 hours after angiography

 

 

 

Length of follow-up:

48-96 hours for laboratory parameters

30 days for clinical events

 

Loss-to-follow-up:

Intervention:

56 (5%)

12 did not receive study drug before angiography

15 were not submitted to angiography

19 were lost to 48-96 hour serum creatinine follow-up

4 died before 48-96 hours

15 did not return to collect serum creatinine

1 was lost to 30-day follow-up

 

Control:

54 (5%)

7 did not receive study drug before angiography

12 were not submitted to angiography

17 were lost to 48-96 hour serum creatinine follow-up

3 died before 48-96 hours

14 did not return to collect serum creatinine

1 was lost to 30-day follow-up

 

 

Incomplete outcome data:

Intervention:

1153 (98%) had data included in laboratory parameters analysis

1171 (99.9%) had data included in secondary outcome analysis

Reasons not reported

 

Control:

1119 (98%) had data included in laboratory parameters analysis

1135 (99.9%) had data included in secondary outcome analysis

Reasons not reported

Outcome measures and effect size (include 95%CI and p-value if available):

 

CI-AKI

(=a 25% elevation of sCr above baseline 48-986 hours after angioplasty)

 

All participants

I: 147/1153 (12.7%)

C: 142/119 (12.7%)

RR: 1.00 (95% CI: 0.81 – 1.25, p=0.97)

 

Patients with serum creatinine >1.5mg/dL:

I: 12/188 (6%)

C: 10/179 (6%)

P=0.75

 

Patients with eGFR 30 – 60 mL/min

I: 30/425 (7%)

C: 27/398 (7%)

RR: 1.04 (0.63 – 1.72)

P=0.73

 

Patients with eGFR<30ml/min

I: 6/56 (11%)

C: 3/48 (6%)

RR: 1.71 (0.45 – 6.49)

P=0.92

 

 

 

Composite outcome of death or need for dialysis:

I: 2,2%

C: 2.3%

Hazard ratio (HR): 0.97 (95% CI: 0.56 – 1.69, p=0.92)

 

Cardiovascular deaths:

HR: 0.99 (95% CI: 0.51 – 1.99, p=0.97)

 

There was also no difference in the risk of these outcomes defined post hoc.

Authors’ conclusion

 

In this large randomized trial we found that acetylcysteine does not reduce the risk of contrast-induced acute kidney injury or other clinically relevant outcomes in at-risk patients undergoing coronary or peripheral vascular angiography.

Castini, 2008

Type of study: randomized controlled trial

 

Setting: elective patients, single centre

 

Country: Italy

 

Source of funding: not reported

Inclusion criteria:

1) patients undergoing CAG and/or PCI

2) age ≥18 years

3) stable sCr ≥1.2mg/dL

 

Exclusion criteria:

1) sCr >4mg/dL

2) a history of dialysis, multiple myeloma, pulmonary edema, cardiogenic shock, acute myocardial infarction

3) emergency catheterization

4) recent exposure to radiographic contrast media within 7 days of the study

5) allergy to iodinate contrast media or NAC

6) previous enrolment in the same or other protocols

7) administration of mannitol, theophylline, dopamine, dobutamine, nonsteroidal anti-inflammatory drugs or fenoldopam

 

N total at baseline:

Intervention: 52

Control: 51

 

Important prognostic factors2:

For example

age ± SD:

I: 71 ± 7

C:73 ± 8

 

Sex:

I: 94% M

C: 84% M

 

sCr (mg/dL)

I: 1.57 ± 0.38

C: 1.49 ± 0.30

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 600mg orally every 12 hours for 2 days

(2 doses before and 2 doses after contrast administration, total dose 2400mg)

 

0.9% saline iv 1ml/kg/hour for 12 hours before and 12 hours after contrast administration

 

Describe control (treatment/procedure/test):

 

 

0.9% saline iv 1ml/kg/hour for 12 hours before and 12 hours after contrast administration

 

Length of follow-up:

5 days

 

Loss-to-follow-up:

none

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN1

(=increase in sCr ≥25% over the baseline value in any of the time points: 24, 48 and 120 hours after contrast administration)

I: 7 (14%)

C: 9 (17%)

p>0.05

 

 

 

CIN2

(=increase in sCr ≥0.5mg/dL over the baseline value in any of the time points: 24, 48 and 120 hours after contrast administration)

I: 4 (8%)
C: 5 (9%)

p>0.05

 

 

 

No acute renal failure necessitating renal replacement therapy occurred.

Authors’ conclusion

 

Our findings suggest that the addition of NAC does not add further benefit in CIN prevention, compared to standard hydration with isotonic saline infusion.

 

Ferrario, 2009

Type of study: randomized controlled trial

 

Setting: elective patients, university hospital

 

Country: Italy

 

Source of funding: not reported

Inclusion criteria:

1) patients scheduled for elective or diagnostic CAG and/or PCI

2) age ≥18 years

3) creatinine clearance <55ml/min and a stable renal function

 

Exclusion criteria:

1) ongoing acute myocardial infarction or acute coronary syndrome

2) renal replacement therapy

3) allergy to NAC

4) need for administration of mannitol, theophylline, dopamine, dobutamine, fenoldopam or nephrotoxic drugs within 1 week of procedure

5) clinical signs of dehydration and systemic hypotension

 

N total at baseline:

Intervention: 99

Control: 101

 

Important prognostic factors2:

For example

age ± SD:

I: 75 ± 8

C: 75 ± 7

 

Sex:

I: 68% M

C: 62% M

 

Creatinine clearance (mL/min)

I: 37 ± 11.5

C: 40 ± 9.3

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 600mg orally every 12 hours for 2 days

(2 doses on the day before and 2 doses on the day of contrast administration, total dose 2400mg)

 

0.9% saline 1ml/kg/h in 12-24 hours before the procedure and 24 hours after

 

 

Describe control (treatment/procedure/test):

 

 

Placebo (glucose tablets) orally every 12 hours for 2 days

(2 doses on the day before and 2 doses on the day of contrast administration)

 

0.9% saline 1ml/kg/h in 12-24 hours before the procedure and 24 hours after

 

Length of follow-up:

3 days

 

Loss-to-follow-up:

Intervention:

4 (4%)

Reasons not reported

 

Control:

4 (3%)

Reasons not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=increase in sCr ≥0.5mg/dL or >25% within 3 days after the procedure)

I: 8/99 (8%)

C: 6/101 (6%)

P=0.60

Authors’ conclusion

 

In our experience, NAC did not prevent CIN in patients receiving iso-osmolar (iodixanol) contrast media and adequate hydration.

Gulel, 2005

Type of study: randomized controlled trial

 

Setting: elective, single centre

 

Country: Turkey

 

Source of funding: not reported

Inclusion criteria:

1) patients scheduled for elective diagnostic CAG

2) chronic renal impairement: sCr >1.3mg/dL

3) stable renal function

 

Exclusion criteria:

1) acute renal failure

2) end-stage renal failure on regular dialysis

3) clinically evident heart failure

4) allergy against contrast agents

5) serious hepatic dysfunction

6) planned PCI

 

N total at baseline:

Intervention: 25

Control: 25

 

Important prognostic factors2:

For example

age ± SD:

I: 61 ± 12

C: 62 ± 12

 

Sex:

I: 80% M

C: 72% M

 

Creatinine clearance (mL/min)

I: 46.5 ± 4.2

C: 43.2 ± 3.9

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 600mg orally every 12 hours for 2 days

(2 doses on the day before and 2 doses on the day of contrast administration, total dose 2400mg)

 

0.9% saline 1ml/kg/h in 12 hours before the procedure and 12 hours after

 

 

Describe control (treatment/procedure/test):

 

 

0.9% saline 1ml/kg/h in 12 hours before the procedure and 12 hours after

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Contrast nephropathy

(= an increase more than 0.5 mg/dL 48 hours after the procedure compared with baseline values-)

I: 3/25 (12%)

C: 2/25 (8%)

p>0.05

Authors’ conclusion:

 

Our results show that oral acetylcysteine does not reduce the risk of contrast nephropathy when used before elective diagnostic CAG in patients with renal dysfunction.

Habib, 2016

Type of study: randomized controlled trial

 

Setting: European Gaza Hospital, Gaza, Palestine (Israel)

 

Source of funding: not reported

Inclusion criteria:

Patients had at least one risk factor for CIN (age >70 years, baseline creatinine level >1.5 mg/dL, heart failure, diabetes mellitus or contrast media volume >300 mL)

 

Exclusion criteria:

Not stated

 

N total at baseline:

Group A: 40

Group C: 40

 

Important prognostic factors2:

For example

age ± SD:

Group A: 63 ± 8

Group C: 63 ± 8

 

Sex:

Group A: 67% M

Group C: 76% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

Group A (n = 30), NAC 1200 mg orally before angiography and 1200 mg orally twice daily for three doses along with good hydration

 

Describe control (treatment/procedure/test):

 

 

Group C (n = 45), hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg/min after angiography or 0.5 mL/kg/h in cases with overt heart failure for 12 h

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

Contrast nephropathy

(= an increase more than 0.5 mg/dL 48 hours after the procedure compared with baseline values-)

I: 2/30

C: 8/45

P=0.001

Authors’ conclusion:

 

Our study indicates that high doses of NAC plus hydration provide better protection against CIN than combination therapy of NAC and ascorbic acid plus hydration, or hydration alone.

Izani Wan, 2008

(Mohamed)

Type of study: randomized controlled trial

 

Setting: elective patients, single centre

 

Country: Malaysia

 

Source of funding: not reported

Inclusion criteria:

1) patients electively admitted for CAG

2) calculated creatinine clearance 40-90ml/min

3) age ≥18 years

 

Exclusion criteria:

1) severe renal failure

2) presence of acute or reversible component of renal failure

3) severe peptic ulcer disease

4) history of allergy to NAC

5) severe asthma

6) pregnancy or breastfeeding

 

N total at baseline:

Intervention: 49

Control: 51

 

Important prognostic factors2:

For example

age ± SD:

I: 58 ± 8

C: 56 ± 7

 

Sex:

I: 86% M

C: 82% M

 

SCr (µmol/L)

I: 124 ± 17

C: 124 ± 22

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 600mg orally every 12 hours for 2 days

(2 doses on the day before and 2 doses on the day of contrast administration, total dose 2400mg)

 

0.45% saline 1ml/kg/h in 12 hours before the procedure and 12 hours after

 

 

Describe control (treatment/procedure/test):

 

 

0.45% saline 1ml/kg/h in 12 hours before the procedure and 12 hours after

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Intervention:

4 (8%)

1 early discharge

2 procedure cancellation

1 procedure complication

 

Control:

4 (7%)

2 early discharge

2 procedure cancellation

 

Incomplete outcome data:

As above

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(= increase of >25% in the sCr level 48 hours after the procedure)

I: 2/49 (4%)

C: 6/51 (12%)

P=0.27

 

None of the patients who developed CIN required dialysis.

Authors’ conclusion:

 

Addition of NAC to standard hydration therapy is not associated with reduction in incidence of CIN in patients with mild to moderate renal impairment undergoing elective CAG.

Koc, 2012

Type of study: randomized controlled trial

 

Setting: elective patients, single centre

 

Country: Turkey

 

Source of funding: not reported

Inclusion criteria:

1) patients about to undergo CAG and/or PCI

2) calculated creatinine clearance <60ml/min or sCr≥1.1mg/dL

3) age ≥18 years

 

Exclusion criteria:

1) contrast-agent hypersensitivity

2) pregnancy or lactation

3) decompensated heart failure

4) pulmonary edema

5) emergency catheterisation

6) acute or end-stage renal failure

 

N total at baseline:

Intervention: 80

Control: 80

 

Important prognostic factors2:

For example

age ± SD:

I: 62 ± 10

C: 65 ± 11

 

Sex:

I: 76% M

C: 79% M

 

Creatinine clearance (mL/min)

I: 59 ± 16

C: 58 ± 16

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

 

NAC 600mg intravenously every 12 hours for 2 days

(2 doses on the day before and 2 doses on the day of contrast administration, total dose 2400mg)

 

0.9% saline iv 1ml/kg/h in on the day before, on the day of, and on the day after the procedure

 

 

Describe control (treatment/procedure/test):

 

 

0.9% saline iv 1ml/kg/h in on the day before, on the day of, and on the day after the procedure

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=baseline sCr ≥25% and/or an absolute increase in sCr of ≥0.5 mg/dL 48 hours after the procedure)

I: 2 (3%)

C: 13 (16%)

P=0.006

 

 

No patients needed hemodialysis.

Authors’conclusion:

 

The results of this study suggest that NAC plus high-dose hydration was superior to high-dose hydration alone as well as standard hydration for the protection of renal function in patients with mild to moderate renal dysfunction who are undergoing CAG and/or PCI.

Kotlyar, 2005

Type of study: randomised controlled trial

 

Setting: elective patients admitted for 1 day

 

Country: Australia

 

Source of funding: commercial (pharmaceutical company)

Inclusion criteria:

1) day-stay elective patients scheduled for CAG and/or PCI

 

Exclusion criteria:

1) allergy to the study medication

2) unstable renal function

3) undergoing chronic dialysis

4) uncontrolled asthma

5) pregnancy or breastfeeding

 

N total at baseline:

I1: 20

I2: 21

C: 19

 

Important prognostic factors2:

For example

age ± SD:

I1: 66 ± 14

I2: 67 ± 12

C: 69 ± 9

 

Sex:

I1: 75% M

I2: 86% M

C: 89% M

 

SCR (mmol/L)

I1: 0.16 ± 0.03

I2: 0.16 ± 0.03

C: 0.15 ± 0.02

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

I1:

NAC 300mg intravenously, once 1-2 hours before procedure and once 2-4 hours after procedure (total dose 600mg)

 

Hydration iv: 0.9% saline 100ml/hour 2 hours before procedure and 5hours after procedure

 

 

I1:

NAC6300mg intravenously, once 1-2 hours before procedure and once 2-4 hours after procedure (total dose 1200mg)

 

Hydration iv: 0.9% saline 100ml/hour 2 hours before procedure and 5hours after procedure

 

Describe control (treatment/procedure/test):

 

Hydration iv: 0.9% saline 100ml/hour 2 hours before procedure and 5hours after procedure

 

Length of follow-up:

2-4 days and 30 days

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

None of the patients developed CIN (=

 

 

None of the patients developed a need for dialysis.

Authors’ conclusion:

 

For day-saty patients with mild to moderate renal impairement undergoing CAG and/or PCI, prehydration alone is less complicated and more cost-effective than a combination of IV NAC (at doses used) and hydration.

Sadineni,

2017

Type of study: randomized controlled trial

 

Setting: Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

 

Source of funding: not reported

Inclusion criteria:

Age more than 30 years +

Patients should have their serum creatinine ≥1.2 mg/dl on their most recent sample drawn within 3 months of planned procedure

 

Exclusion criteria:

Patients with acute renal failure, endstage renal disease requiring dialysis, intravascular administration of contrast material within previous 6 days, pregnancy, lactation, emergent coronary angiography, history of hypersensitivity reaction to contrast media, cardiogenic shock, pulmonary edema, mechanical ventilator, parenteral use of diuretics, recent use of NAC, recent use of ascorbic acid, and use of metformin or NSAIDS within 48 h of procedure were excluded from the study.

 

N total at baseline:

NAC: 35

Placebo: 30

 

Important prognostic factors2:

For example

age ± SD:

NAC: 61 ± 11

Placebo: 63 ± 12

 

Sex:

Group A: 77% M

Group C: 87% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

NAC + NS: Group of patients who received NS and NAC

Describe control (treatment/procedure/test):

 

 

Placebo + NS: Group of patients who received NS only

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN, defined as either a relative increase in serum creatinine from baseline of ≥25% or an absolute increase of ≥0.3 mg/dl (44.2 µmol/L) during days 1 and 2

NAC: 7/35

Placebo: 11/30

P > 0.05

Authors’ conclusion:

 

The major finding of this study was there was no significant difference between NAC and placebo in the prevention of contrast nephropathy.

Seyon, 2007

Type of study: randomized controlled trial

 

Setting: emergency patients, one centre

 

Country: Canada

 

Source of funding: not reported

Inclusion criteria:

1) patients admitted with a diagnosis of acute coronary syndrome

2) scheduled for CAG and/or PCI

3) impaired renal function defined as:

-calculated creatinine clearance <50ml/min or

-sCr≥1.4mg/dL for males or sCr≥1.3mg/dL for females

4) age ≥18 years

 

Exclusion criteria:

1) hemodynamic instability requiring inotropic support

2) pregnancy

3) acute gastrointestinal disorder

4) Killip class III or IV or NYHA III or IV, or patients deemed by cardiologist unsuitable for iv hydration

5) known sensitivity to NAC

6) current treatment with theophylline or mannitol

7) dialysis therapy

8) participation in another study or use of experimental drugs

 

N total at baseline:

Intervention: 20

Control: 20

 

Important prognostic factors2:

For example

age ± SD:

I: 76 ± 6

C: 75 ± 10

 

Sex:

I: 60% M

C: 70% M

 

Groups comparable at baseline? Yes

Describe intervention (treatment/procedure/test):

 

600mg NAC orally four doses in total

(1 before procedure and 3 after every 12 hours)

 

Iv hydration 0.45% saline1ml/kg/hour 4-6 hours before and 12 hours after procedure

 

 

 

Describe control (treatment/procedure/test):

 

Iv hydration 0.45% saline1ml/kg/hour 4-6 hours before and 12 hours after procedure

 

Length of follow-up:

48 hours

 

Loss-to-follow-up:

Not reported

 

Incomplete outcome data:

Not reported

 

 

Outcome measures and effect size (include 95%CI and p-value if available):

 

CIN

(=increase in sCr >44µmol/L (0.5mg/dL) and/or 25% above baseline within 48 hours)

I: 1/20 (5%)

C: 2/20 (10%)

p<0.05

 

 

No patients required dialysis therapy.

 

Authors’ conclusion

 

These results suggest that this cohort gained no added protection to renal function with the use of NAC

Notes:

  1. Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
  2. Provide data per treatment group on the most important prognostic factors [(potential) confounders]
  3. For case-control studies, provide sufficient detail on the procedure used to match cases and controls
  4. For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders

 

CAG: coronary angiography; CECT: contrast-enhanced computed tomography; CI: confidence interval; CI-AKI: contrast-induced acute kidney injury; CIN: contrast induced nephropathy; iv: intravenous; NAC: N-acetylcysteine; NYHA: New York Heart Association; OR: odds ratio; PCI: percutaneous coronary intervention; SCr: serum creatinine

Overwegingen

Our meta-analysis regarding patients with a normal renal function yielded no benefit of NAC for prevention of PC-AKI, both for patients receiving CT scan and/or for patients undergoing CAG.

 

The evidence regarding NAC benefit for prevention of PC-AKI in patients with an impaired renal function is weak due to the quality of the trials and the heterogeneity of the results. For example, follow-up time was only 2 to 5 days in the majority of included studies; thus meaningful conclusions could not be drawn about the consequences of NAC use for mid and long term morbidity and mortality. Furthermore, the studies were not powered to draw conclusions about morbidity and mortality, only for the short-term PC-AKI laboratory diagnosis.

 

A meta-analysis (Sun, 2013) concluded that the evidence on use of IV NAC to prevent PC-AKI was too inconsistent to determine the efficacy. Another meta-analysis concluded that NAC may help to prevent PC-AKI in patients undergoing coronary angiography, but does not have any impact on clinical outcomes such as dialysis or mortality (Submaramiam, 2016). Furthermore, the dose and route of administration of NAC differed between studies. In our own meta-analysis for patients with an impaired kidney function the use of NAC did not decrease the risk of PC-AKI significantly. Of note, only studies that described hydration strategies representative to those used in the Netherlands were included in this analysis. No studies were found that compared oral to intravenous N-acetylcysteine route of administration in patients undergoing intravascular contrast administration.

 

Intervention with NAC is without risk, cheap, and generally available, and there are theoretical arguments that NAC may provide reduction of CI-AKI. Despite the theoretically potential kidney protection arguments, we do not recommend adding NAC to hydration routinely in patients with an impaired kidney function. Reason is that the level of evidence is weak and the demonstrated benefit is small at best, and clinically not proven relevant. Moreover, the low costs of NAC itself is offset by extra handling time and a more complex AKI preventive protocol, which are unnecessary confounding and cost enhancing factors. None of the studies showed significant differences in clinical meaningful endpoints such as need of renal replacement therapy and/or mortality.

Autorisatiedatum en geldigheid

Laatst beoordeeld : 01-11-2017

Laatst geautoriseerd : 01-11-2017

The board of the Radiological Society of the Netherlands will determine at the latest in 2023 if this guideline (per module) is still valid and applicable. If necessary, a new working group will be formed to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be seen as a reason to commence revisions. The Radiological Society of the Netherlands is considered the keeper of this guideline and thus primarily responsible for the actuality of the guideline. The other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.

 

Authotization

The guideline is submitted for authorization to

  • Radiological Society of the Netherlands
  • Netherlands Association of Internal Medicine
  • Dutch Federation of Nephrology
  • Dutch Society of Intensive Care
  • Association of Surgeons of the Netherlands
  • Netherlands Society of Cardiology
  • Netherlands Society for Clinical Chemistry and Laboratory Medicine
  • Netherlands Society of Emergency Physicians
  • Dutch Association of Urology
  • Dutch Society Medical Imaging and Radiotherapy

Initiatief en autorisatie

Initiatief : Nederlandse Vereniging voor Radiologie

Algemene gegevens

The guideline development was assisted by the Knowledge Institute of Medical Specialists (www.kims.orde.nl) and was financed by the Quality Funds for Medical Specialists (Kwaliteitsgelden Medisch Specialisten: SKMS).

Doel en doelgroep

Goal of the current guideline

The aim of the Part 1 of Safe Use of Iodine-containing Contrast Media guidelines is to critically review the present recent evidence with the above trend in mind, and try to formulate new practical guidelines for all hospital physicians to provide the safe use of contrast media in diagnostic and interventional studies. The ultimate goal of this guideline is to increase the quality of care, by providing efficient and expedient healthcare to the specific patient populations that may benefit from this healthcare and simultaneously guard patients from ineffective care. Furthermore, such a guideline should ideally be able to save money and reduce day-hospital waiting lists.

 

Users of this guideline

This guideline is intended for all hospital physicians that request or perform diagnostic or interventional radiologic or cardiologic studies for their patients in which CM are involved.

Samenstelling werkgroep

A multidisciplinary working group was formed for the development of the guideline in 2014. The working group consisted of representatives from all relevant medical specialization fields that are involved with intravascular contrast administration.

 

All working group members have been officially delegated for participation in the working group by their scientific societies. The working group has developed a guideline in the period from October 2014 until July 2017.

 

The working group is responsible for the complete text of this guideline.

  • A.J. van der Molen, radiologist, Leiden University Medical Centre, Leiden (chairman)
  • R.W.F. Geenen, radiologist, Noordwest Ziekenhuisgroep (NWZ), Alkmaar/Den Helder
  • T.H. Pels Rijcken, interventional radiologist, Tergooi, Hilversum
  • H.M. Dekker, radiologist, Radboud University Medical Centre, Nijmegen
  • A.H. van den Meiracker, internist-vascular medicine, Erasmus Medical Centre, Rotterdam
  • E.K. Hoogeveen, nephrologist, Jeroen Bosch Hospital, ‘s-Hertogenbosch
  • H.M. Oudemans - van Straaten, internist-intensive care specialist, Free University Medical Centre, Amsterdam
  • Y.W.J. Sijpkens, nephrologist, Haaglanden Medical Centre, The Hague
  • J. Kooiman, research physician, Leiden University Medical Centre, Leiden
  • C. Cobbaert, clinical chemist, Leiden University Medical Centre (member of advisory board from September 2015)
  • T. Vainas, vascular surgeon, University Medical Centre Groningen (until September 2015)
  • O.R.M. Wikkeling, vascular surgeon, Heelkunde Friesland Groep, location: Nij Smellinghe Hospital, Drachten (from September 2015)
  • P. Danse, interventional cardiologist, Rijnstate Hospital, Arnhem

 

Advisory board

  • K. Prantl, Coordinator Quality & Research, Dutch Kidney Patient Association
  • R. Hubbers, patient representative, Dutch Kidney Patient Association
  • J. Mazel, urologist, Spaarne Gasthuis, Haarlem
  • J. van den Wijngaard, resident in Clinical Chemistry, Leiden University Medical Center
  • A.Y. Demir, clinical chemist, Meander Medical Center, Amersfoort, (member of working group until September 2015)
  • S. Moos, resident in Radiology, HAGA Hospital, The Hague

 

Methodological support

  • I.M. Mostovaya, advisor, Knowledge Institute of Medical Specialists
  • S. Persoon, advisor, Knowledge Institute of Medical Specialists (March 2016 – September 2016)
  • K. Burger, senior advisor, Knowledge Institute of Medical Specialists (until March 2015)
  • A. van Enst, senior advisor, Knowledge Institute of Medical Specialists (from January 2017)
  • J. Boschman, advisor, Knowledge Institute of Medical Specialists (from May 2017)
  • W. Harmsen, advisor, Knowledge Institute of Medical Specialists (from May 2017)

Belangenverklaringen

The working group members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that are related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested at the administrative office of the Knowledge Institute of Medical Specialists and are summarised below.

 

Member

Function

Other offices

Personal financial interests

Personal relationships

Reputation management

Externally financed research

Knowledge-valorisation

Other potential conflicts of interest

Signed

Workgroup

Van der Molen

Chairman, radiologist

Member Contrast Media Safety Committee of the European Society of Urogenital Radiology (unpaid,CMSC meetings are partially funded by CM industry))

None

None

Secretary section of Abdominal Radiology; Radiological Society of the Netherlands (until spring of 2015)

None

None

Receives Royalties for books: Contrast Media Safety, ESUR guidelines, 3rd ed. Springer, 2015

Received speaker fees for lectures on CM safety by GE Healthcare, Guerbet, Bayer Healthcare and Bracco Imaging (2015-2016)

Yes

Geenen

Member, radiologist

Member Contrast Media Safety Committee of the European Society of Urogenital Radiology (unpaid, meetings are partially funded by CM industry)))

None

None

None

None

None

Has been a public speaker during symposia organised by GE Healthcare about contrast agents (most recently in June 2014)

Yes

Dekker

Member, radiologist

None

None

None

None

None

None

None

Yes

Pels Rijcken

Member, interventional radiologist

None

None

None

None

None

None

None

Yes

Danse

Member, cardiologist

Board member committee of Quality, Dutch society for Cardiology (unpaid)

Board member Conference committee DRES (unpaid)

None

None

None

None

None

None

Yes

Oudemans – van Straaten

Member, intensive care medical specialist

Professor Intensive Care

none

None

None

None

None

None

None

Yes

Hoogeveen

Member, nephrologist

Member of Guideline Committee of Dutch Federation of Nephrology

None

None

Member of Guideline Committee of Dutch Society for Nephrology

Grant from the Dutch Kidney Foundation to study effect of fish oil on kidney function in post-MI patients

None

None

Yes

Sijpkens

Member, nephrologist

None

None

None

None

None

None

None

Yes

Van den Meiracker

Member, internist vascular medicine

None

None

None

None

None

None

None

Yes

Cobbaert

Member, physician clinical chemistry

Head of clinical chemistry department in Leiden LUMC.

Tutor for post-academic training of clinical chemists, coordinator/host for the Leiden region

Member of several working groups within the Dutch Society for Clinical Chemistry and member of several international working groups for clinical chemistry

None

None

Member of several working groups within the Dutch Society for Clinical Chemistry and member of several international working groups for clinical chemistry

None

None

None

Yes

Wikkeling

Member, vascular surgeon

None

None

None

None

None

None

None

Yes

Vainas

Member, vascular surgeon

None

None

None

None

None

None

None

Yes

Kooiman

Member, research physician

Resident in department of gynaecology & obstetrics

None

None

None

None

None

None

Yes

Burger

Advisor, Knowledge Institute of Medical Specialists

None

None

None

None

None

None

None

Yes

Mostovaya

Advisor, Knowledge Institute of Medical Specialists

None

None

None

None

None

None

None

Yes

Advisory Board

Prantl

Member, policy maker, Dutch Society of Kidney Patients

None

None

None

None

None

None

None

Yes

Hubbers

Member, patient’s representative, Dutch Society of Kidney Patients

None

None

None

None

None

None

None

Yes

Mazel

Member, urologist

None

None

None

None

None

None

None

Yes

Van den Wijngaard

Member, resident clinical chemistry

Reviewer for several journals (such as American Journal of Physiology)

None

None

None

None

None

None

Yes

Demir

Member, physician clinical chemistry

None

None

None

None

None

None

None

Yes

Inbreng patiëntenperspectief

Patients’ perspective was represented, firstly by membership and involvement in the advisory board of a policy maker and a patients’ representative from the Dutch Kidney Patient Association. Furthermore, an online survey was organized by the Dutch Kidney Patient Association about the subject matter of the guideline. A summary of the results of this survey has been discussed during a working group meeting at the beginning of the guideline development process. Subjects that were deemed relevant by patients were included in the outline of the guideline. The concept guideline has also been submitted for feedback during the comment process to the Dutch Patient and Consumer Federation, who have reported their feedback through the Dutch Kidney Patient Association.

Methode ontwikkeling

Evidence based

Implementatie

In the different phases of guideline development, the implementation of the guideline and the practical enforceability of the guideline were taken into account. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found with the Related Products. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found with the Related Products.

Werkwijze

AGREE

This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0; the advisory committee of the Quality Counsel (www.kwaliteitskoepel.nl). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreetrust.org), a broadly accepted instrument in the international community and on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).

 

Identification of subject matter

During the initial phase of the guideline development, the chairman, working group and the advisor inventory the relevant subject matter for the guideline. Furthermore, an Invitational Conference was organized, where additional relevant subjects were suggested by the Dutch Kidney Patient Association, Dutch Society for Emergency Physicians, and Dutch Society for Urology. A report of this meeting can be found in Related Products.

 

Clinical questions and outcomes

During the initial phase of guideline development, the chairman, working group and advisor identified relevant subject matter for the guideline. Furthermore, input was acquired for the outline of the guideline during an Invitational Conference. The working group then formulated definitive clinical questions and defined relevant outcome measures (both beneficial land harmful effects). The working group rated the outcome measures as critical, important and not important. Furthermore, where applicable, the working group defined relevant clinical differences.

 

Strategy for search and selection of literature

For the separate clinical questions, specific search terms were formulated and published scientific articles were sought after in (several) electronic databases. Furthermore, studies were looked for by cross-referencing other included studies. The studies with potentially the highest quality of research were looked for first. The working group members selected literature in pairs (independently of each other) based on title and abstract. A second selection was performed based on full text. The databases search terms and selection criteria are described in the modules containing the clinical questions.

 

Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search, so that risk of bias could be estimated. This is described in the “risk of bias” tables.

 

Summary of literature

The relevant research findings of all selected articles are shown in evidence tables. The most important findings in literature are described in literature summaries. When there were enough similarities between studies, the study data were pooled.

 

Grading the strength of scientific evidence

A) For intervention questions

The strength of the conclusions of the scientific publications was determined using the GRADE-method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org/) (Atkins, 2004).

 

GRADE defines four gradations for the quality of scientific evidence: high, moderate, low or very low. These gradations provide information about the amount of certainty about the literature conclusions. (http://www.guidelinedevelopment.org/handbook/).

 

F1

 

B) For diagnostic, etiological, prognostic or adverse effect questions, the GRADE-methodology cannot (yet) be applied. The quality of evidence of the conclusion is determined by the EBRO method (van Everdingen, 2004)

 

Formulating conclusion

For diagnostic, etiological, prognostic or adverse effect questions, the evidence was summarized in one or more conclusions, and the level of the most relevant evidence was reported. For intervention questions, the conclusion was drawn based on the body of evidence (not one or several articles). The working groups weighed the beneficial and harmful effects of the intervention.

 

Considerations

Aspects such as expertise of working group members, patient preferences, costs, availability of facilities, and organization of healthcare aspects are important to consider when formulating a recommendation. These aspects were discussed in the paragraph Considerations.

 

Formulating recommendations

The recommendations answer the clinical question and were based on the available scientific evidence and the most relevant considerations.

 

Constraints (organization of healthcare)

During the development of the outline of the guideline and the rest of the guideline development process, the organization of healthcare was explicitly taken into account. Constraints that were relevant for certain clinical questions were discussed in the Consideration paragraphs of those clinical questions. The comprehensive and additional aspects of the organization of healthcare were discussed in a separate chapter.

 

Development of quality indicators

Internal (meant for use by scientific society or its members) quality indicators are developed simultaneously with the guideline. Furthermore, existing indicators on this subject were critically appraised; and the working group produces an advice about such indicators. Additional information on the development of quality indicators is available by contacting the Knowledge Institute for Medical Specialists. (secretariaat@kennisinstituut.nl).

 

Knowledge Gaps

During the development of the guideline, a systematic literature search was performed the results of which help to answer the clinical questions. For each clinical question the working group determined if additional scientific research on this subject was desirable. An overview of recommendations for further research is available in the appendix Knowledge Gaps.

 

Comment- and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The commentaries were collected and discussed with the working group. The feedback was used to improve the guideline; afterwards the working group made the guideline definitive. The final version of the guideline was offered for authorization to the involved scientific societies, and was authorized.

 

References

Atkins D, Eccles M, Flottorp S, et al. GRADE Working Group. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The GRADE Working Group. BMC Health Serv Res. 2004 Dec 22;4(1):38.

Van Everdingen JJE, Burgers JS, Assendelft WJJ, et al. Evidence-based richtlijnontwikkeling. Bohn Stafleu van Loghum. Houten, 2004

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