Statins and noncardiac surgery: Current evidence and practical considerations
ABSTRACT
Vascular surgery is associated with a high risk of perioperative morbidity and mortality that is partly attributable to inflammatory stress induced by the surgical procedure. Preoperative initiation of a long-acting statin is a strategy intended to reduce the inflammatory stress response and the excess risk associated with vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III demonstrated significant reductions in perioperative myocardial ischemia and the composite end point of myocardial infarction or cardiovascular death with extended-release fluvastatin (relative to placebo) initiated 30 days prior to vascular surgery. These benefits were achieved with no increase in liver dysfunction, evidence of myopathy, or other side effects. Observational data suggest that perioperative statin use is associated with improved recovery from acute kidney injury after high-risk vascular surgery and with improved long-term survival in patients undergoing such surgery.
KEY POINTS
- The inflammatory and oxidative stress induced by vascular surgery can be blunted by statin therapy.
- Statin therapy started preoperatively can reduce the incidence of myocardial ischemia and the level of inflammatory markers in patients undergoing high-risk vascular surgery.
- The purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery, with the long-term goal being achievement of target lipid levels.
- A long-acting statin is preferred preoperatively to best extend the anti-inflammatory effects into the postoperative period. Statin therapy should be continued postoperatively, if possible, to avoid deleterious acute withdrawal effects.
ANOTHER POTENTIAL BENEFIT: ENHANCED RECOVERY OF KIDNEY FUNCTION
Postoperative renal dysfunction is an ominous sign
Renal ischemic reperfusion injury is inevitable after vascular surgery that requires aortic cross-clamping. This is significant, as renal dysfunction after surgery is an ominous long-term sign that indicates abundant atherosclerosis. Complete recovery after acute kidney injury portends an improved long-term outcome, whereas patients with persistent renal dysfunction after vascular surgery have poor long-term outcomes.
A benefit from statins?
Statins may offer an effective means of preventing or shortening the course of acute kidney injury after surgery. Statins have been reported to lengthen survival of chronic kidney disease patients with sepsis or infectious complications and to improve the course of acute kidney injury in aging rats.13–15 These findings prompted my colleagues and I to conduct a retrospective study to evaluate whether statins may ameliorate reperfusion injury in the kidney after aortic cross-clamping.16
Promising findings from an observational review
We reviewed the records of all patients who had undergone vascular surgery at Erasmus Medical Center from January 1995 to June 2006 to examine the relation between preoperative statin use and renal function after suprarenal aortic cross-clamping.16 Of the 1,944 patients who met inclusion criteria, 515 (26.5%) were statin users. Postoperative kidney injury was defined as more than a 10% reduction in creatinine clearance on postoperative day 1 or 2 compared with baseline. Recovery of kidney function was defined as a creatinine clearance of greater than 90% of the baseline value by postoperative day 3.
The clinical characteristics of the populations with and without kidney injury after aortic cross-clamping were similar, including baseline creatinine clearance and serum creatinine.
Acute kidney injury within 2 days of surgery occurred in 664 patients (34%), of which 313 (47%) had complete recovery of kidney function at postoperative day 3. Although the incidence of postoperative kidney injury was similar among statin users and nonusers, statin use was associated with an increased chance of complete recovery of kidney function at day 3 (odds ratio = 2.0; 95% CI, 1.0–3.8).
All-cause mortality was assessed during a mean follow-up of 6.24 years. Statin use was associated with improved long-term survival, regardless of any change in kidney function (hazard ratio for death = 0.60; 95% CI, 0.48–0.75). Among the four broad patient groups, survival was highest among statin users with no postoperative kidney injury, followed by statin users who had kidney injury, then by nonusers of statins with no kidney injury, and finally by nonusers of statins who had kidney injury.
We concluded that perioperative statin use was associated with clinically significant recovery from acute kidney injury after high-risk vascular surgery and, more importantly, with improved long-term survival regardless of the presence of kidney injury. These promising findings require confirmation in prospective trials.
SUMMARY
Vascular surgery carries a high risk of perioperative mortality. Perioperative use of extended-release fluvastatin is associated with a reduced incidence of myocardial ischemia and the composite of MI and cardiovascular death at 30 days following surgery. These beneficial clinical outcomes are achieved without an increase in the incidence of side effects, including liver dysfunction and myopathy. Preoperative initiation of a long-acting statin is a reasonable strategy for reducing the risks associated with vascular surgery, and offers a bridge to postoperative statin continuation to blunt the inflammatory stress of surgery. Ischemic reperfusion injury is a major cause of renal dysfunction following vascular surgery. Statin therapy appears to help restore kidney function after aortic cross-clamping in patients undergoing high-risk vascular surgery.
DISCUSSION
Question from the audience: The majority of patients randomized in DECREASE III had relatively normal cholesterol levels. Do you believe those patients are biologically different from patients with physiologic vascular disease and elevated cholesterol levels?
Dr. Poldermans: We enrolled patients with various baseline cholesterol levels, and we found that these levels were not related to postoperative outcome. It would be a good idea to examine inflammation status just prior to surgery in patients with lower cholesterol levels to see if they have different outcomes from those with high cholesterol.
Question from the audience: If a patient is already on a short-acting statin and we know that he or she won’t be able to take a statin postoperatively, should we change to a long-acting statin just prior to surgery?
Dr. Poldermans: To be honest, this is a financial issue. If you have the opportunity, the best course would be to prescribe a statin with a prolonged half-life or an extended-release formulation. Of course, it’s not always possible to prescribe one particular statin. You have to negotiate what is feasible and hope to initiate the statin as early as possible to reduce risk.
Question from the audience: In studies conducted outside the perioperative setting, such as PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) and a substudy of REVERSAL (Reversing Atherosclerosis with Aggressive Lipid Lowering), it took about 30 days after statin initiation for hsCRP levels to minimize, and at least that long for halting of plaque progression to be detected by intravascular ultrasonography. Given that, does it make sense to delay nonurgent surgery in a patient in whom you’re worried about a postoperative MI?
Dr. Poldermans: Rat studies show improved blood flow and reduced thrombosis within hours of statin initiation. In the perioperative setting, therefore, initiating a statin within 30 days may be appropriate, but nobody knows the exact timing for optimal effect. Since there are no data to answer this question, I would not postpone surgery for this reason.
