PRESERVE: No Benefit from Sodium Bicarbonate, Acetylcysteine After Angiography

Deborah Brauser

November 12, 2017

ANAHEIM, CA — Neither intravenous (IV) sodium bicarbonate nor oral N-acetylcysteine (NAC) significantly reduces adverse outcomes in patients at high risk for renal complications undergoing angiography, new research suggests[1].

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial included almost 5000 high-risk patients from 53 centers in the US, Australia, Malaysia, and New Zealand scheduled to undergo angiography.

All were randomly assigned, in a 2-by-2 factorial design, to receive IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride plus NAC or placebo. The primary outcome was a composite of death, need for dialysis, or an increase over baseline of at least 50% in serum-creatinine level 90 days postangiography.

At a prespecified interim analysis, there were no significant benefits found from either study agent, and the trial was prematurely stopped.

Results at that point showed that 4.4% of those receiving sodium bicarbonate reached the primary end point vs 4.7% of those receiving sodium chloride, and in 4.6% vs 4.5% of the NAC and placebo groups, respectively.

Secondary outcomes, including contrast-associated acute kidney injury (AKI) and persistent kidney impairment up to 90 days, also did not differ significantly between the groups.

Dr Steven D Weisbord

"These interventions were not effective at all compared with their comparators in patients with chronic kidney disease undergoing these procedures," lead author Dr Steven D Weisbord (Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, PA) told Medscape Cardiology.

"The findings should immediately impact how providers perform angiograms in this patient population," said Weisbord.

The findings were presented here today at the American Heart Association (AHA) 2017 Scientific Sessions and were simultaneously published online in the New England Journal of Medicine.

Asked to comment, Dr Umesh N Khot (Cleveland Clinic, OH) said this was important research into a common problem.

"Many of these patients who need angiography combined with having baseline bad kidneys are between a rock and a hard place," said Khot, who was not involved with this research.

"We're in the position of talking with them about saving their hearts but potentially sacrificing their kidneys. So this is an important topic, but the results are quite stunning because the things we've been trying don't work," he said.

Past Results Mixed

As previously reported, serious adverse events such as AKI have been associated with the contrast material used during angiographies.

"The periprocedural administration of intravenous isotonic sodium chloride has been the standard intervention to prevent this complication," write the investigators.

"On the basis of hypotheses that urinary alkalinization and scavenging of reactive oxygen species mitigate renal tubular epithelial-cell injury from the use of iodinated contrast material," past studies have compared sodium bicarbonate with this standard intervention, as well as assessing the benefit of using NAC.

Although results have been mixed, there has still been "widespread use in clinical practice" for these interventions, the researchers write.

Weisbord noted that the end point in most of these studies has been blood-creatinine increases, but they wanted to look at a harder end point in a very large patient population.

"There have been dozens of studies looking at these interventions in the past, and most were relatively small, used a surrogate outcome, and had very divergent findings," he said.

"There hasn't really been any sound evidence for their use, so that was the motivation for us to design a much bigger study, look at high-risk patients, and look at much more serious outcomes," said Weisbord. "We did not want to design this to look at a primary end point that constitutes a small change in kidney function within a short period of time after a procedure."

Enrollment Stopped

In February 2013, the investigators began enrolling patients with chronic kidney disease at 71 sites in five countries, with a planned cohort of 7680.

At the preplanned interim analysis, the data and safety monitoring committee recommended that trial enrollment be stopped because of a lack of significant differences between the groups for the primary outcome, which the study's sponsor accepted. Enrollment was stopped on March 31, 2017 with 5177 patients entered into the study.

"Even with conservative assumptions, there was less than 12% likelihood that that the findings would change and that there would be a statistically significant finding favoring one of the interventions," said Weisbord.

Of the 4993 participants (94% men; mean age 69.8 years; 81% with diabetes mellitus) included in the modified intention-to-treat analysis, 2511 were randomly assigned to receive sodium bicarbonate and 2482 to receive sodium chloride. Each group also received either 1200 mg twice daily of NAC capsules for 5 days, beginning about 1 hour prior to angiography (n=2495) or matching placebo (n=2498).

Preangiography, the IV fluids were administered 1- to 3-mL/kg/h over 1 to 12 hours up to a total volume of 3 to 12 mL/kg. Intra-angiography, the fluids were administered 1- to 1.5-mL/kg/h. Postprocedure it was 1- to 3-mL/kg/h over 2 to 12 hours up to a total volume of 6 to 12 mL/kg.

There were no significant differences in patient characteristics among the groups.

In the full group of participants, 90.5% vs 9.5% underwent coronary and noncoronary angiography, respectively; and a mean volume of 85 mL of contrast material was administered. The mean baseline eGFR was 50.2, with a mean baseline SCr of 1.5.

"Shuts the Door" on Interventions

Results showed that 110 of the patients receiving sodium bicarbonate in any combination and 116 of those receiving sodium chloride reached the composite primary end point (odds ratio [OR] 0.93, 95% CI 0.72–1.22; P=0.62); as did 114 vs 112 of the NAC and placebo groups, respectively (OR 1.02, 95% CI 0.78–1.33; P=0.88).

In addition, 239 vs 206 (P=0.13) and 228 vs 217 (P=0.58) of the groups, respectively, had contrast-associated AKI.

There were no significant between-group differences in the secondary outcomes of death by day 90, need for dialysis by day 90, all-cause hospitalization by day 90, and persistent renal impairment.

"In prespecified subgroups, there were also no significant differences considering multiple comparisons," said Weisbord.

Although this trial was stopped early, it was still "twice as large" as the largest previous trial of NAC and "much larger" than past studies assessing IV sodium bicarbonate, note the investigators.

"We specifically wanted to look at what we refer to as 'MAKE-D,' which is major adverse kidney events and death," said Weisbord. "We found that neither of the interventions decreased the rate of our 90-day primary outcome and didn't decrease the rate of kidney injury, either."

He added that the findings "should now shut the door" on any further studies of these particular interventions for this purpose.

"Our study showed that the standard of care, in regard to the prevention of contrast-associated acute kidney injury and adverse outcomes and at least in regard to IV fluids, isotonic saline or sodium chloride is the appropriate intervention," said Weisbord.

"There's no role for sodium bicarbonate and acetylcysteine in this way. We established that not only is neither intervention effective, there also isn't a potential benefit in adding acetylcysteine to bicarbonate."

What Now?

Khot later commented to Medscape Cardiology that the study had several main strengths: its large size, "the rigor in terms of what they used for defining the follow-up," hard end points, and the follow-up data.

"But the unanswered question is: now what? I think this definitively answers about the interventions, but what do we do with these patients now?" he asked. "It closes one set of doors completely, but it also opens a whole set of other issues. We still have a problem with these patients; that didn't go away. So what are the other options?"

He noted that some people have suggested adjusting fluid status, or possibly using vitamin C in some way. No matter what, Khot said it's important to minimize contrast volume exposure.

He congratulated the investigators on "trying to answer practical questions in a real-life way. These questions are extremely important and have great bearing in the day-to-day."

At a press briefing, official discussant Dr Nuria M Pastor-Soler (Keck School of Medicine at the University of Southern California, Los Angeles) agreed, noting that the study answered "an important clinical question."

Study strengths she listed included its international enrollment, use of a "sliding scale" protocol for administration of fluids, and that clinically relevant end points were used.

Limitations cited for PRESERVE included the predominantly male patient population, "which is to be expected in a primarily VA-patient group," that the study enrollment had been stopped for futility, and that a sliding scale was used for fluid dosage.

She noted that potential next steps could include evaluating the same end points in the participants at a longer follow-up or evaluating other differences between the treatments, such as biomarkers of acute and persistent kidney damage or in the settings of emergency angiography procedures or radiographic/angiographic procedures needing larger administrations of IV contrast. Sex differences would also be interesting, said Dr Pastor-Soler.

"Overall, this is an important study that helps resolve the uncertainty of how best to manage and preserve kidney function in patients undergoing angiography and receiving contrast dye," she summarized.

"It showed that neither the type of fluids given during the procedure nor the use of antioxidant therapy appears to significantly affect outcomes, especially kidney outcomes, in this population."

The study was funded by the US Department of Veterans Affairs Office of Research and Development and by the National Health and Medical Research Council of Australia. Weisbord reports receiving personal fees from Durect outside the submitted work. Disclosures for the coauthors are listed on the journal website. Khot reports no financial disclosures with this study but was on an advisory board for a meeting a few years ago for AstraZeneca. Pastor-Soler reported being chair of the Kidney Council for the American Heart Association, copresident of Women in Nephrology, and on the editorial boards of the American Journal of Physiology and Frontiers in Renal and Epithelial Physiology.

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