Of the 1902 patients who met study criteria, 1119 (58.8%) were treated with preoperative statin therapy. Patient baseline characteristics are summarised in Table 1. Patients on preoperative statins were more likely to be older (mean age 65.4 years vs 59.9 years, P<0.001), have diabetes mellitus, hypercholesterolaemia, left main coronary artery disease, a higher BMI, and higher Canadian Cardiovascular Society angina score. A total of 1098 (57.7%) patients were propensity-score matched (preoperative statins: n=551 and patients not on statins: n=547). The baseline characteristics of the propensity-score matched cohort are summarised in Table 2; all characteristics between those treated and untreated with statins, including the bypass and cross clamp time, were not significantly different. Regarding statin therapy administered (after propensity matching), 308 (55.9%) patients received atorvastatin 40mg daily, 52 (9.4%) received atorvastatin 80mg, 108 (19.6%) received rosuvastatin 20mg daily, 55 (10.0%) received rosuvastatin 40mg daily, 19 (3.4%) received pravastatin 40mg and 9 (1.6%) received simvastatin 40mg daily.
Univariable analysis of the primary outcomes:
The difference in postoperative outcomes between patients with and without preoperative statin therapy using univariable logistic regression are summarised in Table 3 and Figure 1. Patients on preoperative statin therapy were associated with a significantly reduced risk of surgical site infections (0.7% vs 13.9%, OR 0.045, 95%CI 0.016-0.125, P<0.001) and pneumonia (38.3% vs 52.5%, OR 0.562, 95% CI 0.442-0.716, P<0.001) compared to those untreated with preoperative statin. There were no significant differences in the rates of wound infection and pneumonia when compared to the type and dose of statin therapy.
Univariable analyses of the secondary outcomes:
Preoperative statin use was associated with a significantly higher risk of prolonged (≥4 hours) inotrope requirement (30.3% vs 20.8%, OR 1.652, 95% CI 1.255-2.175, P<0.001) and new-onset atrial fibrillation (14.2% versus 9.7%, OR 1.537, 95% CI 1.061-2.227, P=0.023) after surgery than those untreated with statin (Table 3 and Figure 1). Although the duration of mechanical ventilation was similar between the two groups, the length of ICU (40.7 hrs vs 46.0 hrs, P=0.001) and hospital stay (9 days vs 10 days, P=0.016) were both significantly shorter in patients treated with preoperative statins than those who were not treated with statin. There were no significant differences in any of the secondary outcomes when compared to the type and dose of statin therapy.
Preoperative statin use was associated with a reduced risk of surgical site infections (OR 0.01, 95% CI 0.001-0.075, P<0.001) and pneumonia (OR 0.359, 95% CI 0.278-0.464, P<0.001) after adjusting for other covariates (Table 4). The association between statin use and prolonged inotrope requirement remained largely unchanged after adjusting for the significant covariates in Table 1 (OR 2.113, 95% CI 1.612-2.770, P<0.001).
Subgroup analysis of patients undergoing non-CABG surgery:
Among those who had non-CABG surgery, no patients who were treated with preoperative statins developed surgical site infections compared to 12 (6%) surgical site infections among patients who were untreated with preoperative statins. The incidence of pneumonia was also significantly lower among those treated with preoperative statins (31.9% vs 49.8%, OR=0.603, 95% CI 0.391-0.932, P=0.017) than those untreated with statin Table 5 and Figure 2). Statin use was also associated with a reduced risk of 30-day mortality (1.5% vs 5.5%, OR=0.106, 95% CI 0.014-0.812, P=0.028)(Table 5). The duration of mechanical ventilation, and ICU and hospital stay were not significantly different between those treated and untreated with preoperative statin in patients who had non-CABG surgery.
Subgroup analysis of patients undergoing off-pump CABG surgery:
In patients undergoing off-pump CABG surgery, prolonged inotrope requirement was not significantly different between the statin (50.0% vs 37.5%, OR 1.667, 95% CI 0.854-3.253, P=0.133) and the non-statin groups (Table 6). Similarly, the risk of developing new-onset atrial fibrillation after surgery was not significantly different between the two groups (21.4% versus 11.1%, OR 2.182, 95% CI 0.860-5.534, P=0.100).
Although the effects of statin therapy on perioperative outcomes have been studied, its specific effect on perioperative infections has not been thoroughly investigated. Infections were reported as an outcome in seven randomised-controlled-trials assessing the benefits of perioperative statin in cardiac surgery.(20) Of these seven trials, only two (with a total of 2537 patients) were deemed to have a low risk of bias with a suggestion that statin use was associated with a statistically insignificant reduced risk of infection compared to placebo (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.60-1.07; P=0.14). Given infection is an important cause of morbidity after cardiac surgery and short-term perioperative statin therapy is a relatively inexpensive therapy, it is paramount to establish whether preoperative statin can reduce surgical site infections and pneumonia in cardiac surgery.
This study found that preoperative statin therapy was associated with a significantly reduced risk of postoperative surgical site infections and pneumonia in adult patients undergoing cardiac surgery. The benefits remained significant after multivariable analysis on the propensity-matched cohort. In the subgroup of patients who had non-CABG cardiac surgery (i.e. valve and/or aortic procedures), preoperative statins remained significantly associated with a reduced risk of pneumonia, surgical site infections, and more importantly, also 30-day mortality. These results are clinically relevant and require careful consideration.
Previous studies have shown that diabetes mellitus, smoking, impaired left ventricular function, urgency of the procedure and type of procedure are predictors of infective complications after cardiac surgery.(25-27) Whether preoperative statin therapy can reduce infective complications after cardiac surgery remains, however, uncertain. Current guidelines recommend that statin therapy should be continued until the day of cardiac surgery due to its cholesterol-lowering effect and long-term mortality benefits in patients with ischaemic heart disease.(28) Our results support this recommendation, and provide a possible additional explanation why continued use of statin preoperatively is important. Statins are known to modulate the inflammatory and immune responses. It is well established that cardiac surgery and the institution of cardiopulmonary bypass can provoke a vigorous inflammatory response through the activation of multiple inflammatory response modifiers, including several interleukins and tumour necrosis factor-alpha (TNF-α).(29) Excessive inflammation will induce ischaemic-reperfusion injury and production of reactive free radicals, leading to cell membrane injury, tissue damage and in severe cases, even organ failure.(30) Although statin has been shown to reduce inflammation and improve wound healing,(17,18,31) its potential benefits on perioperative clinical outcomes after cardiac and non-cardiac surgery have been less forthcoming and certainly far from conclusive.(4-7, 32-36) Our results add weight to support the hypothesis that statin may have some clinically-important anti-infective effects.
Although statin is inexpensive, it still has some well-documented side effects (e.g. deranged liver function test and myalgia) and also potential serious harmful effects, including inducing acute kidney injury.(4-7) Our results also raise the (unexpected) concerns that statin may increase the risk of new-onset atrial fibrillation and LCOS. It is important to recognise that LCOS state was defined as prolonged inotrope requirement greater than four hours based on the ANZSCTS database. Given the variability in the management of LCOS amongst intensivists, this definition of prolonged LCOS may not reflect a true representation. Post-operative atrial fibrillation and LCOS are multifactorial processes and given the limitations of our study, our results should be interpreted with caution. As such, an adequately powered multicentre randomised controlled trial - stratified by whether the patient is undergoing CABG or non-CABG surgery - is paramount before preoperative statin is used as a prophylactic agent against infections in cardiac surgery.
Finally, we need to emphasize the limitations of this study. Although our study utilised prospectively collected data including the primary and secondary outcome endpoints, the definition of pneumonia (as defined by the ANZSCTS database) was broad and hence there was overall increased incidence of pneumonia. Furthermore, data regarding patients’ plasma cholesterol levels were not available at the time of the surgery. As with any observational studies, any association between intervention and outcome should only be concluded as association and not necessarily causal in nature, and residual confounding is always possible.
In summary, our results showed that preoperative statin use was associated with a reduced risk of surgical site infections and pneumonia after cardiac surgery. In the subgroup of patients undergoing non-CABG surgery, preoperative statin use was associated with a reduced risk of 30-day mortality. Our findings support the current guidelines in recommending continuation of statin therapy prior to cardiac surgery. An adequately-powered, double-blinded, randomised-controlled-trial with infections as the primary outcome is needed to confirm the hypothesis that statin - a relatively easy and cheap intervention – is safe and effective in reducing different types of infections after cardiac surgery.