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PRESERVE: No benefit of sodium bicarbonate, acetylcysteine for prevention of mortality, renal outcomes after angiography
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ANAHEIM, Calif. — Among patients with chronic kidney disease undergoing angiography, a strategy of IV sodium bicarbonate or oral acetylcysteine yielded no additional benefit for the prevention of death, dialysis or persistent kidney impairment at 90 days, researchers reported at the American Heart Association Scientific Sessions.
Trials and meta-analyses evaluating interventions to prevent contrast-associated kidney injury, particularly the administration of IV sodium bicarbonate and oral acetylcysteine, have largely been underpowered and have yielded divergent or inconclusive findings, according to Steven Weisbord, MD, MSc, associate professor of medicine and clinical and translational science, renal-electrolyte division, University of Pittsburgh School of Medicine.
“As a result of that, there is widespread utilization of these interventions in clinical practice, despite the fact that there is persistent clinical equipoise,” he said during a press conference.
Lack of benefit
To more definitively investigate the benefits of these interventions, Weisbord and colleagues conducted the international PRESERVE trial. Using a 2-by-2 factorial design, patients with impaired kidney function undergoing coronary or noncoronary angiography were randomly assigned to receive IV 1.26% sodium bicarbonate (n = 2,511), IV 0.9% sodium chloride (n = 2,482), 5 days of oral acetylcysteine (n = 2,495) or placebo (n = 2,498).
The primary endpoint was a composite of death, the need for dialysis and a persistent increase in serum creatinine of at least 50% at 90 days. The most important secondary endpoint was contrast-associated acute kidney injury, Weisbord noted.
“Unlike most prior studies that looked at small changes in kidney function after procedures to determine whether the intervention was effective, we specifically designed this study to look at patient-centered outcomes at 90 days,” he said.
In terms of the primary endpoint, there were no significant differences between the sodium bicarbonate group compared with the sodium chloride group (4.4% vs. 4.7%; OR = 0.93; 95% CI, 0.72-1.22). Similar results were seen in comparison of the acetylcysteine group with the placebo group (4.6% vs. 4.5%; OR = 1.02; 95% CI, 0.78-1.33).
The researchers also found no difference in contrast-associated acute kidney injury, between the sodium bicarbonate and sodium chloride groups (9.5% vs. 8.3%; OR = 1.16; 95% CI, 0.96-1.41) or between the acetylcysteine and placebo groups (9.1% vs. 8.7%; OR = 1.06; 95% CI, 0.87-1.28).
Rates of other secondary endpoints also did not differ between groups.
Prespecified subgroup analyses yielded similar results.
The PRESERVE trial was conducted at 53 sites in Australia, Malaysia, New Zealand and the United States. Patients qualified for inclusion if they had stage 3 or 4 CKD or less severe CKD with diabetes.
A total of 4,993 patients were included in the intention-to-treat analysis. The mean age of patients was 70 years, 93.6% were men, 81% had diabetes and 90.5% were undergoing coronary angiography. The median serum creatinine level at baseline was 1.5 µg/dL and the median estimated glomerular filtration rate was 50.2 mL/min/1.73 m2. There were more Hispanic patients assigned to sodium bicarbonate group than the sodium chloride group (4.3% vs. 2.9%; P = .008), but no other differences were noted across treatment groups.
Clinical implications
The trial’s target sample size was 7,680 patients, but the sponsor — the VA Office of Research and Development and the National Health and Medical Research Council of Australia — stopped the trial after the enrollment of 5,177 patients based on the results from a prespecified interim analysis.
“Based on the results to date and conditional analyses demonstrating that even with conservative assumptions, there was a less than 12% likelihood that we would find a statistically significant finding in the opposite direction of results to date with full enrollment of the target sample size,” Weisbord said.
These data, he noted, indicate that sodium bicarbonate is not more effective than sodium chloride nor is acetylcysteine more effective than placebo for prevention of serious outcomes or acute kidney injury after angiography.
“The current standard of care based on these findings is that the prevention of contrast-associated acute kidney injury and adverse outcomes should include the administration of IV sodium chloride, or saline, in patients who are at high risk, and there is no role for administration of N-acetylcysteine,” Weisbord said. – by Melissa Foster
References:
Weisbord S. LBS.01: CABG and EP Peri-procedural Dilemmas. Presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, California.
Weisbord SD, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1710933.
Disclosure: Weisbord reports no relevant financial disclosures.
Perspective
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C. Michael Valentine, MD, FACC
PRESERVE has great relevance to interventional cardiologists who have been searching for the holy grail of renal preservation in patients at high risk for angiography- and contrast-induced renal failure. For many years, we have tried sodium bicarbonate and acetylcysteine but did not know whether our results were effective and whether patients were benefiting. This study finally closes the door on that question of whether sodium bicarbonate or acetylcysteine will improve outcomes for our patients.
This is the definitive paper. It will change therapy and behavior immediately.
Perspective
Back to TopNúria M. Pastor-Soler, MD, PhD, FASN
The PRESERVE trial has many strengths. It was a double-blind, placebo-controlled trial on an important clinical question that had been previously studied without consistent results. The trial had international enrollment as well as a clear rationale and study design that was presented in a separate publication. The main question was: Is there a benefit of urine alkalization and the use of scavenging or antioxidant agents to prevent contrast-induced acute kidney injury?
Other strengths include the researchers’ use of a “sliding-scale” protocol for fluid administration, the use of routine angioplasty procedures, and the use of very clinically relevant endpoints with important sequelae in the kidney and overall, such as death.
The PRESERVE trial also had some limitations, which were generally minimal. For instance, they used a centralized lab for VA blood samples, while they had no choice but to use local labs for urine samples. Another limitation as the fact that study enrollment was stopped at an interim point based on a regulatory recommendation of the VA panel based on conditional power analyses for futility of continuation of the study, as discussed by Dr. Weisbord. Additionally, by chance, more Hispanic patients were assigned to the sodium bicarbonate group and the overall population was predominantly male due to the fact that most patients were drawn from VA hospitals. One more limitation, which was also minor, was the sliding scale for fluid dosage that was capped for the highest BMI category.
Potential next steps include longer follow-up to see if the results remain consistent with regards to the primary and secondary endpoints; evaluation of differences between treatments in biomarkers of kidney damage, in the setting of emergency procedures and in the setting of radiographic or angiographic procedures requiring larger loads of IV contrast; and evaluation of sex differences in the outcomes after IV contrast administration among the treatments studied in the PRESERVE trial.
Overall, this is an important study that helps resolve the uncertainty of how best to manage and preserve kidney function in patients who undergo angiography and receive contrast dye. The findings show that neither type of fluids given at procedure nor use of antioxidant therapy appears to affect outcomes and especially kidney outcomes in this population.
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