As a kid growing up in the San Francisco ACT brought to mind guys in tights running around and projecting their voices at the American Conservatory Theater. Now I’ve got to adjust my association with the acronym with the recent publication in Circulation of the Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT).
ACT is the largest randomized trial to date to evaluate the use of oral acetylcysteine prophylaxis in patients at risk for contrast induced nephropathy (CIN). In this multicenter trial, 2803 patients at risk for CIN undergoing an intravascular angiographic procedure were randomized to either acetylcysteine or placebo. Roughly 35% of patients in each group had eGFRs between 30-60 ml/min by MDRD and about 5% in each group had an eGFR of less than 30 ml/min.
The acetylcysteine group received 1200 mg of oral acetylcysteine q12 hours before and after the contrast load. The use of normal saline at a rate of 1 mL/kg per hour, from 6 to 12 hours before to 6 to 12 hours after angiography, was strongly recommended but changes in the total volume or speed of administration were permitted. In the end, 94% of patients received normal saline in both the treatment and placebo groups at some dose with 47% in both groups receiving exactly the recommended dose.
There was no difference between the treatment and placebo arms in terms of the primary outcome of CIN (defined as a 25% elevation of serum creatinine above baseline between 48 and 96 hours after angiography) or the secondary composite outcome of need for dialysis or death in the intention to treat analysis. Approximately 13% of patients in each group experienced CIN with 2% and 0.3% experiencing death or need for dialysis respectively.
This looks to be the end of the acetylcysteine in CIN argument. It’s hard to imagine a larger or more well performed study. There was no hint in the subgoups that patients with more severe chronic kidney disease or diabetic nephropathy might benefit. This is clear evidence that we should drop acetylcysteine from the CIN prophylaxis tool kit and focus our efforts elsewhere.
So, the argument is not over. As noted in the commentary, the ACT results are limited by the low resolution of the description of the fluid strategies between groups leaving the bias door open a crack. The issue of generalizability is also raised in patients with advanced chronic kidney disease (and other high risk groups) given their relatively low numbers in the study. Although the ACT subgroup analyses give no hint that NAC might be of benefit in these groups the hypothesis of benefit for them remains to be adequately tested.
At the last ASN meeting, Steve Weisbord from Univ of Pittsburgh, national expert in CIN, already criticized the results of this study based on the inclusion of small amounts of patients at high risk for CIN. I believe oral NAC is harmless and cheap and should still be used as a complement of IV isotonic fluids.
The subgroup analysis is very much underpowered, making it hard to draw any major conclusions from it – agreed, it should be treated as hypothesis generating only.
This was very much an opportunity missed to answer the NAC question in higher risk populations – perhaps a two-by-two factorial design with NAC vs placebo and saline vs bicarb would have provided more more value and robustness to the trial design and ultimate interpretation.
Volume prophylaxis is paramount – but in a person with SCr of 3, with 1-2g proteinuria, who is heading for angiography, it seems that the additional benefit (or not) of NAC remains unclear. Unfortunately, the question may never be answered and individual decisions must be made for each case, based on the treating physician's assessment of risk/benefit.
A much more detailed review of ACT is up over at The Kidney Doctor.
There, Dr Singh also questions the level of detail provided on the volume strategy and the generalizability of the results to patients at high risk for CIN. I think the issue of generalizability in the high risk group is a relevant one, that as he states, requires more study.
Still leaves open the question of what's to be done with this group in the meantime…
Good points. They don't give a perfect picture of the volume given but they give quite a good one (median hours of pre and post fluid, percentage who got NS at 1ml/kg for 6 hours and so on).
At the granularity they provide there were no differences between NAC or placebo groups in volume strategy. As you point out it would have been nice to have subgroup level detail here (the Supplement unfortunately does not have it).
There was no suggestion of benefit in any of the subgroups evaluated (CKD, DMII, higher volume of contrast) with the caveat of small numbers. The meta-analysis included with the study suggests no benefit of NAC in the pooled data of studies with reported adequate methodologies.
Given the above (negative results in studies with adequate methodologies), as we move forward I would think we would treat the idea that NAC might prevent CIN in advanced CKD or other high risk conditions as a hypothesis to be tested rather than a therapeutic default.
I'd be interested in your thoughts.
The ACT trial had only 180 patients in each arm with creatinine values above 1.5, limiting our ability to generalize these findings to a true high-risk population with pre-existing CKD. Also, unfortunately they did not enforce a required study fluid regimen for each participant. Despite randomization, we are not informed of the amount and rate of volume prophylaxis between groups – given that volume has the best evidence in preventing CIN, this is a further limitation in assessing the true effect of NAC from this study. Finally, the contrast volumes were not overly substantial, leaving questions in relation to potential benefit in the setting of larger contrast loads. Despite the strong points of this study, it seems premature to make firm conclusions in relation to populations that the findings can not be generalized to.
It will be interesting to see how long it takes NAC to drop out of practice.
My guess is even with ACT we're sill going to be hearing about NAC for a while. I still get calls to "dialyze post IV contrast load" to prevent CIN. Seems to be an area where we need to work on educating and innovating.
Yet another diversion from the core issue of why are HOCM and gadolinium so widely *tolerated* today, and even newer agents unacceptably toxic.
We also pretend as if this CIN is just "temporary" despite a substantial percentage who *never* return to baseline, and deceive ourselves into believing that we need only "concern" ourselves for those patients "at risk" for CIN, and deceive ourselves into thinking that 5-10% (general population) of patients is a "rare" occurrence not to worry about.
Finally! In my view, NAC has caused considerable indirect harm over the years by the removing the focus from pre-hydration in patients at risk for CIN. The amount of times I've heard "No, we didn't give any fluids beforehand, but don't worry – they got N-Acetylcysteine!" Gah!