STICS: No Benefit to Perioperative Statin Therapy in Cardiac Surgery, but Acute Kidney Injury Risk Increased

Statin therapy given in the lead-up to elective cardiac surgery and in the days after the procedure fails to prevent postoperative atrial fibrillation and myocardial damage, according to the results of a large trial. In fact, the perioperative use of statin therapy increases the risk of acute kidney injury, a finding that caught researchers by surprise.

The results suggest that while the administration of statins does produce a measurable, albeit mild, anti-inflammatory and antioxidant effect, it does not result in a clinical benefit for patients undergoing cardiac surgery and might even cause harm, according to the investigators.

Speaking with TCTMD, senior investigator Barbara Casadei, MD (University of Oxford, England), said the results should have an impact on clinical practice, particularly since guidelines currently recommend perioperative statin therapy for the prevention of atrial fibrillation and other in-hospital complications after surgery. Instead, Casadei recommends stopping statins prior to surgery and restarting in the days after the procedure. 

“The beneficial effects of statins are really proven for the long-term, sustained reduction of LDL cholesterol levels,” she said. “You start to see the splitting of the [event] curves after 6 months, and in the first year the effect is always smaller than in the subsequent years. So, if you stop the statin for a week, it’s not going to increase your risk [of ischemic events]. It would only increase your risk if the so-called pleiotropic effects of statins, which would have a rapid onset, were relevant. We have demonstrated that they’re not, unfortunately.”

The study, known as the STICS (Statin Therapy in Cardiac Surgery) trial, was first presented at the European Society of Cardiology 2014 Congress in Barcelona, Spain, and is now published in the New England Journal of Medicine.

The STICS Study

Statins have been postulated as a potential treatment to reduce the risk of postoperative complications, because inflammation and oxidative stress have been implicated in the onset of atrial fibrillation and other complications after surgery. Atrial fibrillation, said Casadei, is a significant adverse event that results in increased morbidity and mortality, which translates into longer hospital stays and increased costs.

“It’s very common,” she said. “It’s not killing the patients, but it’s prolonging hospitalization. It’s making the postoperative hospital stay rockier, because they are already hemodynamically unstable.”

The STICS study included 1,922 patients in normal sinus rhythm scheduled for cardiac surgery and randomized patients to treatment with rosuvastatin 20 mg or placebo up to 8 days before surgery and for 5 days after the procedure. After cardiac surgery—87% of patients underwent CABG and the remainder aortic-valve replacement—the postoperative incidence of new-onset atrial fibrillation was 21% in patients treated with rosuvastatin and 20% in patients treated with placebo, a nonsignificant difference. Regarding the coprimary endpoint of myocardial injury—as assessed by troponin I concentrations—treatment with rosuvastatin had no significant effect of troponin I release after surgery. 

Acute kidney injury, however, was significantly more common among patients treated with rosuvastatin, with most of the excess driven by an increase in stage 1 acute kidney injury. There was also a significant 80% relative increase in the risk of stage 2/3 acute kidney injury among those treated with rosuvastatin compared with those receiving placebo.

“It was definitely unexpected, because when you look at the meta-analyses of all of the trials in primary and secondary prevention with statins, there is really no effect on kidney injury,” said Casadei. “There is certainly no signal that in these patients [statin therapy] has any adverse effect on the kidney.”

Although surprising, Casadei pointed to a study published February 2016 in the Journal of the American Medical Association. In that study, the overall results showed similar rates of acute kidney injury in cardiac surgery patients treated perioperatively with atorvastatin. However, in the patients who were statin-naive prior to surgery, treatment with atorvastatin led to a nonsignificant excess of acute kidney injury. Moreover, among statin-naive patients with preexisting chronic kidney disease, there was a significant increase in acute kidney injury among those treated with atorvastatin.

For Casadei, “this suggests that the adverse effect on renal function in this group of patients is not limited to rosuvastatin.”

Making Sense of the Field

To TCTMD, Casadei noted that in studies where statins were stopped for up to 3 months in the run-in phase of clinical trials, there has been no evidence of an increase in cardiovascular events during that time. This is important as most patients undergoing CABG or valve surgery are likely being treated with a statin for secondary prevention. Given that the beneficial effects of statins emerge in the 6 to 12 months after initiating therapy, she recommends stopping the statin at 1 to 2 days prior to cardiac surgery and starting again after a few days. Although the risk of kidney injury is relatively small—an absolute increase of 5%, most of the increase mild—there is nothing to be gained from perioperative statin therapy, she said.

Islam Elgendy, MD (University of Florida, Gainesville), who was not involved in the STICS trial, published a meta-analysis in the Annals of Thoracic Surgery in January that showed statin therapy started anywhere from a week to 21 days before surgery significantly improved clinical outcomes after CABG surgery. In that analysis, starting statins before surgery was associated with a 58% lower risk of postoperative atrial fibrillation.

To TCTMD, Elgendy said there are two possibilities for the lack of benefit in the STICS trial, the first being that rosuvastatin might differ from atorvastatin and not prevent postoperative atrial fibrillation. For example, in their meta-analysis, although they included the STICS trial, most of the benefit was seen in trials testing atorvastatin 20 mg or 40 mg. “We know from prior statin trials that there are drug therapy differences between the classes,” he said. “The [A-fib] benefit has been consistent with atorvastatin.”

In addition, Elgendy noted that STICS started treatment 8 days before surgery, whereas most of the other trials showing a benefit gave statins much earlier. “Most of the studies that had shown benefit, including prior meta-analyses, all showed that the longer the statin therapy was started the more the benefit,” he said. “Maybe in STICS, just starting the statin for a shorter duration may have resulted in the negative result.”

He pointed out that patients are started on statins, if they’re not already taking the drugs, before cardiac surgery because they have coronary artery disease, with the goal being to reduce the risk of future ischemic events but not necessarily atrial fibrillation after surgery.

For her part, Casadei doesn’t think the lack of benefit in their trial is attributable to the drug, noting that some of the earlier smaller studies suggested rosuvastatin could also reduce the postoperative risk of atrial fibrillation. She said that previous studies have suggested perioperative statin therapy could “massively” reduce that risk, with some reports showing reductions of 50% or greater. However, the earlier signal of benefit is typical of scientific research, where a cluster of small studies, often uncontrolled and some retrospective, show benefit but are later challenged when a large-scale randomized clinical is performed, she said.

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