Baseline serum albumin and body mass index were excluded from the model estimating propensity scores because many values were missing (43% and 30%, respectively). Furthermore, 881 patients with missing values for ≥1 of the other baseline variables included in the model estimating propensity scores were removed. Our propensity-matching procedure yielded successful matches for 4172 (87%) of the statin users; therefore, our analyzed dataset consisted of 8344 propensity-matched patients.
Before matching, statin users were generally older and sicker than nonusers in baseline characteristics (Table 1). After matching, none of the baseline potential confounders exhibited absolute standardized difference scores >0.2 (Fig. 2). Although serum albumin and body mass index were not considered in the matching, they were nonetheless well balanced among the matched patients with available measurements. Thus, the propensity-matching procedure was successful in balancing baseline potential confounders. Intraoperative characteristics such as case duration and fluid volumes, also not used for propensity matching, were nonetheless similar among the matched patients (Table 1).
The incidence (95% confidence interval) of AKI was 7.1% (6.2%, 8.1%) in the matched statin users and 8.0% (7.1%, 9.0%) in the nonusers, corresponding to an OR of 0.88 (0.75, 1.03), which was not statistically significant (P = 0.12, χ2 test).
The secondary outcomes were also not significantly different between matched statin users and nonusers. Postoperative dialysis was required for 0.10% (0.02%, 0.33%) and 0.12% (0.04%, 0.37%) of patients in the matched groups (OR = 0.80 [0.16, 3.70]; P = 0.74). In-hospital mortality occurred in 1.0% (0.7%, 1.5%) and 1.3% (0.9%, 1.8%) of the matched patients, respectively (OR = 0.76 [0.47, 1.20]; P = 0.18). A summary of the incidence of primary and secondary outcomes among statin users and nonusers (both before and after matching) is provided in Table 2.
Our principal finding is that preoperative statin therapy does not seem to be associated with a reduced risk of AKI in patients undergoing noncardiac surgery (although, as our confidence interval for the primary comparison of interest indicates, we could not exclude from possibility a reduction in the odds of AKI as large as 25%). This result is similar to that reported in patients having noncardiac25 and cardiac surgery.26 In contrast, Molnar et al.27 reported an association between preoperative statin use and a reduced risk of AKI in patients having major elective surgery. However, their study cohort was restricted to patients older than 65 years of age. Furthermore, they combined patients having cardiac and noncardiac surgery, although pathophysiologic mechanisms for AKI probably differ.5,28 Most importantly, however, Molnar et al. used AKI diagnostic codes based on the International Classification of Diseases, Ninth Revision classification system, which has only 28% sensitivity for AKI.29
We also found no evidence supporting the idea that preoperative statin use is associated with a reduced incidence of new-onset dialysis or hospital mortality. The same results were reported in a single-center, albeit smaller, retrospective study by Kor et al.25 in patients undergoing major vascular surgery. A recent study associating statin use with a lower incidence of new-onset dialysis also reported an absence of association between statin use and reduced dialysis dependence 90 to 120 days postoperatively, making a significant long-term renoprotective effect of statin drugs in current clinical doses highly unlikely.27
A “healthy user effect” referring to the phenomenon in which patients who adhere to a medication schedule also engage in a healthy lifestyle, resulting in better overall health,31 can explain the reduction in hospital mortality reported by Lindenauer et al. in patients receiving a lipid-decreasing drug. Another explanation is that the sample size of this study was not large enough to detect a difference between the 2 groups. A post hoc sample size calculation suggests that approximately 27,000 patients per group would be necessary to exclude a type II error in assessing the effects of statin therapy on hospital mortality (assuming 90% power and an OR of ≤0.7).
Available evidence suggests that routine preoperative statin use has little if any renoprotective effect.25,26,32 In fact, there are currently no known effective and safe drugs that prevent ischemic renal injury.33–36 Maintaining adequate arterial blood pressure might thus be the best clinical approach at this time.37 It remains possible, however, that current doses of statins, mainly used to treat hypercholesterolemia, are insufficient in attenuating AKI. Consistent with this theory, Verma et al.38 demonstrated attenuation of cell injury with pravastatin, but only at high serum concentrations of the drug.11
Although statin drugs are restarted on the first postoperative day according to an institutional protocol, the possibility of late reinstitution of statin drugs in some patients (because of postoperative ileus or surgical team preference) cannot be excluded and may have potentially masked a protective effect of statins. “Statin withdrawal” can occur when the drugs are discontinued postoperatively, or reinstituted >48 hours after surgery. Statin withdrawal is thought to augment the risk of AKI, new-onset dialysis, and hospital mortality.25 Le Manach et al.39 also reported that postoperative statin withdrawal for at least 4 days is an independent predictor of postoperative cardiac myonecrosis.
Our registry does not include specific statin formulations, doses, or preoperative duration of use. Potency varies among statins and molecules that cause comparable lipid decreasing may differ considerably in their antiinflammatory characteristics and ability to prevent atrial fibrillation and provide other cardiac benefits.40 It thus remains plausible that adequate doses of certain statins could provide substantial protection against AKI, but this will be determined only by focused, prospective, randomized, controlled studies.
As with any observational study, our results are subject to potential selection bias, confounding, and measurement bias.31 In addition, 40% of our patients were excluded because of missing data (Fig. 1).We attempted to limit these sources of error by using propensity matching. Because the Perioperative Health Documentation System is mostly based on clinical (rather than administrative) records, it is fairly dense and includes many known predictors of AKI. Nonetheless, it remains likely that at least some unknown confounders impaired our analysis. Intraoperative hemodynamic variables may have differed between the 2 groups and could have influenced the incidence of AKI.36 We note, however, that important confounding factors mostly increase the likelihood of spurious associations, rather than cause lack of association as we found.
In summary, we did not identify an independent association between preoperative statin therapy at current clinical doses used for treatment of hypercholesterolemia and risk of AKI, postoperative dialysis, or hospital mortality in patients having noncardiac surgery.
a HCUP Clinical Classifications Software (CCS) for ICD-9-CM. Available at: http://www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp. Accessed January 7, 2011.
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