CURRICULUM IN CARDIOLOGY - JOURNAL CLUB

Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 122-125

Outcomes after angiography with sodium bicarbonate and acetylcysteine

Aayush Kumar Singal, Bharath Raj Kidambi
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Dr. Aayush Kumar Singal
Department of Cardiology, 7^th Floor, CN Centre, All India Institute of Medical Sciences, New Delhi - 110 029
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/jpcs.jpcs_34_18

Citation

Background

• Patients with cardiac diseases often have underlying kidney disease also
• Attempting diagnostic/therapeutic procedures requiring radiocontrast dyes can potentially save the heart, but at the cost of worsening renal functions
• Contrast-associated-acute kidney injury (CA-AKI) is defined as an increase in serum creatinine ≥0.3 mg/dL, or ≥25% from baseline, within 48 h
• Attempts to find therapy, which can mitigate this dye-related damage, have been ongoing for the last 20 years
• Initial small single-center studies suggested the benefits of N-acetyl cysteine (NAC)^[2] and sodium bicarbonate.^[3]
• Since then, >100 studies on NAC and >50 on sodium bicarbonate have been published
• In the last 3 years itself, seven systematic reviews have been done, but still the question as to the efficacy of these agents remains unanswered
• Of these reviews, some^[4],[5],[6] favored the use of NAC and some^[7] suggested that there was a beneficial effect of sodium bicarbonate. To oppose these, there were many reviews which suggested that these agents were not useful in protection against CA-AKI^[8],[9],[10]
• To answer this clinical conundrum on a topic of such great clinical significance, the PRESERVE trial was planned.

• Double blinded
• International, multicentric (4 countries, 53 sites: the United States of America [35 Veterans Affairs sites], Australia [13 sites], Malaysia [3 sites], and New Zealand [2 sites])
• Placebo and comparator drug controlled
• 2 × 2 factorial design
• Enrollment: February 2013 through March 2017
• Target sample size: 7680
• Funding – US Department of Veterans Affairs Office, National Health and Medical Research Council of Australia.

• Undergoing elective coronary or noncoronary angiography
• Estimated glomerular filtration rate (eGFR) of 15–44.9 ml/min/1.73 m² or
• eGFR of 45–59.9 ml/min/1.73 m² among those with diabetes mellitus
• Able and willing to provide informed consent.

• Emergency angiography (defined as need for angiogram within 3 h of initial clinical presentation)
• Unstable baseline levels of blood creatinine (defined as increase or decrease of ≥25% within 3 days before angiography)
• Receiving dialysis, or chronic kidney disease 5
• Decompensated heart failure
• Receipt of iodinated contrast in the past 5 days
• Known allergy to acetylcysteine or iodinated contrast
• Pregnancy.

• Compared with isotonic intravenous (IV) NaCl, isotonic IV NaHCO₃ decreases serious adverse outcomes following angiography
• Compared with placebo, oral NAC decreases serious adverse outcomes following angiography.

• 1⁰ end point
• Composite of death, need for dialysis, or persistent increase in serum creatinine ≥50% at 90 days.
• 2⁰ end points
• CA-AKI (increase in serum creatinine ≥0.5 mg/dL or ≥25% at 3–5 days)
• Individual components of 1⁰ end point
• Hospitalization for heart failure, stroke, and acute coronary syndrome by 90 days
• All-cause hospitalization.

Methods

• Estimated sample size: 7680
• Trial was stopped after 5177 patients (67%) were randomized because of results from preplanned interim analysis, according to which, even with conservative assumptions, there was <12% likelihood that the findings would change and that there would be a statistically significant finding favoring one of the interventions.
• A total of 4993 patients were included in the final analytic cohort.

• IV fluids (1.26% NaHCO₃, 0.9% NaCl)
• Preangio: 1–3 mL/kg/h over 1–12 h → total volume 3–12 mL/kg
• Intra-angio: 1–1.5 mL/kg/h
• Postangio: 1–3 mL/kg/h over 2–12 h → total volume 6–12 mL/kg
• Local providers specified rate, duration, and volume of these parameters.
• NAC/placebo capsules
• 1200 mg po bid × 5 days starting ~ 1 h prior to angiography.

• An equal number of patients were randomized into the four study arms: sodium bicarbonate, NAC, placebo, or sodium chloride
• Protocol-defined amounts of IV fluids were administered
• Blood samples were taken at baseline, between 3 and 5 days, and between 90 and 104 days (maximum up to 180 days).

• Modified intention-to-treat analysis was used
• For baseline and procedural characteristics, t-test, Wilcoxon rank sum test, and Chi-square test were used
• For interaction between NaCl and NaHCO₃, multivariate logistic regression model was utilized
• O'Brien–Fleming multiple testing procedure was used for conducting the interim analysis, which was done after 50% of the estimated number of patients had been followed through for 90 days
• P ≤ 0.05 was considered to indicate statistical significance for the interaction term and for analysis of primary and secondary outcomes
• Overall analysis was done using the SAS software, version 9.4 (SAS Institute, North Carolina State University, JMP).

Results

• The baseline demographics and procedural details were similar across different study arms
• Mean age was 69.8 years, and 93.6% were men
• 80.9% were diabetics
• Baseline median serum creatinine was 1.5 mg/dL, and the median eGFR was 50.2 mL/min/1.73 m²
• Nearly 90.5% of patients underwent coronary angiography, while 9.5% underwent noncoronary angiography. Percutaneous coronary intervention was done in 28.5% of patients
• Median contrast volume used was 85 mL
• Iodixanol, a nonionic iso-osmolar radiocontrast agent, was used most frequently (>55% cases).

• Sodium bicarbonate and sodium chloride did not vary with respect to the primary end point (4.4 vs. 4.7, odds ratio [OR] 0.93 [95% confidence interval CI: −0.72–1.22] P = 0.62)
• NAC was not better than placebo for the primary outcome (4.6 vs. 4.5, OR 1.02 [95% CI − 0.78–1.33] P = 0.88)

• None of the secondary end points were different in sodium bicarbonate versus sodium chloride groups
• NAC was not better than placebo for any of the secondary outcomes.

Discussion

• IV NaHCO₃ is not more effective than IV NaCl for prevention of serious outcomes or AKI following angiography
• NAC is not effective in the prevention of serious outcomes or AKI following angiography
• The current standard of care for prevention of CA-AKI and associated adverse outcomes should be IV isotonic NaCl. There is no role of NAC for the same.

• This study studied a highly relevant research question that is of paramount clinical importance, yet whose answer had remained ambiguous till before this study
• This was a double-blinded, multicentric trial with robust methodology and low risk of bias
• This study has recruited the largest sample size till date on this topic. Their trial population was more than twice as large as the population in the largest previous trial of acetylcysteine and much larger than the populations in all the previous trials of IV sodium bicarbonate
• Hard primary end points, Major Adverse Kidney Events and Death, were studied, unlike the previous trials, which relied on clinical surrogate outcomes
• Patients with preserved renal functions were excluded. This overcame the potential dilution of the efficacy of interventions, which was a serious flaw in the previous studies. Compared from ACT study (acetylcysteine for Contrast-Induced Nephropathy trial),^[11] where inclusion of many patients with preserved kidney function limited the generalizability of the results.

Limitations

• Primary end point assessment was done at 90 days. Thus, any intervening event such as coronary artery bypass grafting could have masked the benefits of the trial intervention. However, the fact that neither study intervention showed benefit with respect to CA-AKI suggests that this chance event was not statistically significant
• For assessment of CA-AKI, serum creatinine was measured at a single time point. Thus, patients with a rise occurring beyond the specified time interval were missed. Also, the study missed patients having a transient decrease in renal functions
• Since the recruitment of patients was predominantly done from Veteran Affairs hospitals, the study recruited males disproportionately, thus raising question on generalized applicability of the results to female population. However, this male preponderance is in keeping with the natural distribution of cardiac diseases and the ratio of males: females undergoing diagnostic/therapeutic interventions
• This study only enrolled patients undergoing angiography, thus raising a question on generalizability of the findings for patients undergoing other procedures involving iodinated contrast material. However, such a doubt lacks a scientific plausibility
• The design protocol excluded 6642 potentially eligible patients before randomization, reflecting a potential source of bias
• A standard protocol for IV fluid administration was not followed. All the patients did not receive identical fluid volumes. However, similar fluid volume was used across different groups
• Relatively small volumes of contrast were used (mean 85 ml), and percutaneous interventions were performed in only ~28% of cases. This may account for the lesser than expected number of patients developing CA-AKI.

Table 1: Critical appraisal of the PRESERVE trial Click here to view

Conclusion

• These findings reaffirm the fact that expensive treatment options may not necessarily be better than conventional methods
• Small underpowered single-center studies should be regarded with skepticism until results from well-designed, randomized controlled clinical trials are available
• The PRESERVE trial results have effectively put an end to any further studies of these particular interventions for this purpose.

References

1.	Weisbord SD, Gallagher M, Jneid H, Garcia S, Cass A, Thwin SS, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018;378:603-14.
2.	Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180-4.
3.	Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: A randomized controlled trial. JAMA 2004;291:2328-34.
4.	Kang X, Hu DY, Li CB, Ai ZS, Peng A. N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with pre-existing renal insufficiency or diabetes: A systematic review and meta-analysis. Ren Fail 2015;37:297-303.
5.	Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: A systematic review and meta-analysis. Ann Intern Med 2016;164:406-16.
6.	Xu R, Tao A, Bai Y, Deng Y, Chen G. Effectiveness of N-acetylcysteine for the prevention of contrast-induced nephropathy: A systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2016;5. pii: e003968.
7.	Zhang B, Liang L, Chen W, Liang C, Zhang S. The efficacy of sodium bicarbonate in preventing contrast-induced nephropathy in patients with pre-existing renal insufficiency: A meta-analysis. BMJ Open 2015;5:e006989.
8.	Loomba RS, Shah PH, Aggarwal S, Arora RR. Role of N-acetylcysteine to prevent contrast-induced nephropathy: A meta-analysis. Am J Ther 2016;23:e172-83.
9.	Zapata-Chica CA, Bello Marquez D, Serna-Higuita LM, Nieto-Ríos JF, Casas-Arroyave FD, Donado-Gómez JH, et al. Sodium bicarbonate versus isotonic saline solution to prevent contrast-induced nephropathy: A systematic review and meta-analysis. Colomb Med (Cali) 2015;46:90-103.
10.	Zhao SJ, Zhong ZS, Qi GX, Tian W. The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: A meta-analysis of randomized controlled trials. Int J Cardiol 2016;221:251-9.
11.	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;124:1250-9.