Statins to prevent acute kidney injury after cardiac surgery

Statins, is there anything they can’t do? These agents, granted blockbuster status more than 20 years ago, are potent weapons in our fight against cardiovascular disease. But beyond their cholesterol-lowering effects, we’ve seen studies where statins act as anti-inflammatories, improve immune function and even stave off dementia.  Could the wonder-drugs prevent acute kidney injury, a dreaded complication after cardiac surgery, associated with more than a three-fold increase in mortality?

For the video version of this post, click here.

Full disclosure: I research acute kidney injury, or AKI. So welcome to my world, statins – a world where positive clinical trials are as rare as an epidemiologist at a Mr. Personality contest.

The trial, out of Vanderbilt university hospital appeared in JAMA and enrolled 617 individuals undergoing cardiac surgery. The treatment group got 80mg of atorvastatin prior to surgery, and 40mgs a day after that. The placebo group got, well, placebo. As you might imagine, the majority of patients (400) were already taking a statin.  In that case, if you were randomized to placebo, you only got placebo for the day of surgery and the day after. After that, you were back on your home statin dose.

And to boil the results down to a word: nothing. The rate of AKI was 21% in the statin arm and 20% in the placebo arm. Looking at secondary outcomes, there were no differences in rates of death, dialysis, delirium, stroke, or stay in the ICU.

This might be expected in the group that was already on statins – after all, skipping two days of the drug might not be enough to make a real difference. But if we look at the statin-naïve group, the rate of AKI was 22% in the statin group and 13% in the placebo group. This was not statistically significant but the trend here is clearly in the wrong direction. In fact, if we look at absolute creatinine change –where higher levels are worse- those on the statin had a small, but statistically significant increase in creatinine compared to those on placebo.

But take these numbers with a grain of salt. The data safety and monitoring board forced the study authors to stop recruitment of statin-naïve patients about 2/3rds of the way through the study. They did this because they saw a signal of harm from statins in that group. So the fact that we see harm may be biased by the DSMBs choice to stop that part of the study early.

Now, would I have stopped the study if I were on the DSMB?  Probably. The odds that continuing to recruit would show a benefit of statin were really low, and you don’t want to expose patients to potential harm. But despite that, we can’t accept the results of an early-termination arm of a trial with the same gusto that we would had the trial continued to completion.  In short, the jury is still out as to whether statin use is actually harmful in terms of AKI. But I can say for now I’m pretty convinced it ain’t helping anybody.

Give beta-blockers pre-op. Wait... don't. Well, maybe.

For the video version of this post, click here. When I was training as a medical resident, we used to do all these consults for perioperative clearance, or, more politically, perioperative risk-stratification.  The idea is that, before elective surgery, we’d go in and take a detailed history and decide if the patient needed any additional workup before they went under the knife.  Not infrequently, we’d suggest perioperative beta-blockade.  The idea was that the stress of surgery put a strain on the heart, and the beta-blockers would prevent post-op cardiac complications.

The rationale for this behavior was bolstered by something called the DECREASE IV trial, which randomized pre-operative patients to get a beta-blocker or placebo, and showed that those who got the beta-blocker were significantly less likely to experience a cardiac event. But a subsequent trial, called POISE, found that those who got beta-blockers had an increased risk of all-cause mortality.  It also emerged that the DECREASE trial had serious ethical flaws, and that some of the data may have been fabricated.  

Still, the biologic rationale is there, so what do we do?  Well, a paper appearing in JAMA-internal medicine attempts to answer this question, albeit in a very roundabout way.  Let’s see if we can get there.

Danish researchers used that country’s impressive electronic health record database to identify 55,320 individuals who underwent non-cardiac surgery between 2005 and 2011. This number excluded anyone with any sort of heart disease, though all of the patients had hypertension.  In fact, they were all taking at least two anti-hypertensives, which makes this a rather unique cohort to begin with. It turned out that the 30-day mortality risk was 1.93% in those taking beta-blockers compared to 1.32% in those taking other anti-hypertensives. This relationship persisted even after adjustment for things like age, sex, surgical risk, and comorbidities. So… case-closed? We shouldn’t give people beta-blockers pre-operatively?

Well, not so fast. This study only looked at those who were already taking beta-blockers - it doesn’t really tell us anything about what happens if you start a beta-blocker pre-op. Moreover, people get beta-blockers for a reason. That reason often involves some practitioner deciding the patient is at risk of some type of cardiac event, meaning the deck might have been stacked against beta-blockade from the beginning.  Also, restricting the cohort to those on two anti-hypertensives really limits what we can apply to most patients.

The American College of Cardiology currently recommends keeping patients on beta-blockers perioperatively if they were already on beta-blockers. I’d be very surprised if this study leads to any sort of change of heart.