Are statins cardioprotective in patients undergoing major vascular surgery?

After noncardiac vascular surgery, the most common causes of morbidity and mortality are cardiac complications. Among patients undergoing major vascular surgery, statins have been shown to exert cardioprotective effects^1-3 above and beyond their cholesterol-lowering effects.⁴ We evaluated whether intensive statin therapy and lower cholesterol levels resulted in better outcomes among subjects undergoing vascular surgery. We also assessed whether statins have cardioprotective effects regardless of cholesterol level.

Subjects and methods

Between 2002 and 2006, a total of 359 patients who underwent elective noncardiac vascular surgery were enrolled in the study. Subjects who participated in clinical intervention trials (ie, the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo [DECREASE]-II, -III, and -V trials) were excluded. Baseline characteristics were documented at the start of the study, including the statin drug, dose (which was converted to the percentage of maximum recommended therapeutic dose), and duration of use. Statin therapy for a duration of 3 months or more before surgery was considered long-term therapy. Beta blockers were considered in all subjects before surgery to obtain perioperative heart rates of 60 to 65 beats/minute. One day before surgery and for up to 2 days after surgery, all subjects were monitored with a 12-lead digital electrocardiogram recorder. A period of reversible ST-segment changes lasting for at least 1 minute and shifting from baseline to > 0.1 mV (1 mm) was considered to be an occurrence of ischemia. On postoperative days 1, 3, and 7, and whenever indicated by electrocardiographic changes, we assessed troponin T levels.

Long-term and 30-day major cardiac events (nonfatal myocardial infarction [MI] and cardiac death) were the study end points. Subjects with development of at least 2 of the following symptoms (new Q waves [> 1 mm or > 30 ms], typical symptoms of angina pectoris, and increased cardiac enzyme levels) were diagnosed with nonfatal MI. Death caused by sudden death, congestive heart failure, cardiac arrhythmias, or acute MI was considered cardiac death. To assess the effect of cholesterol levels and statin dose on 30-day clinical cardiac outcome, troponin T release, and perioperative MI, we performed binary logistic regression analysis. The association between statin dose and cholesterol levels with late cardiac events was assessed with Cox proportional hazard analysis. To correct for selection bias, we calculated a propensity score for statin therapy, which was created using multiple logistic regression analysis. Adjustments were made for propensity scores, baseline characteristics, sex, and age using multivariate analysis.

Figure 1. Incidence of myocardial ischemia and troponin T release. The lowest

incidence of myocardial ischemia and troponin T release in the perioperative period

was observed in patients with statin doses of more than 50% of the maximum

recommended therapeutic dose.

Figure 2. Incidence of myocardial ischemia and troponin T release. The incidence of

myocardial ischemia and troponin T release in the perioperative period was lowest in

patients with baseline low-density lipoprotein (LDL) cholesterol levels below 80 mg/dL.

Results

Seventy-nine percent of the study sample was male, and the mean age was 67 ± 10 years. Among the 187 subjects (52%) who received statin therapy, 7 took rosuvastatin (Crestor), 35 took fluvastatin (Lescol), 42 took pravastatin (Pravachol), 49 took atorvastatin (Lipitor), and 54 took simvastatin (Zocor). A total of 150 subjects (42%) were receiving long-term therapy; statins were newly prescribed for 37 subjects (10%). The mean statin dose was 41% ± 32% of the maximum recommended therapeutic dose. Compared with subjects who were not taking statins, those receiving statins had a history of cerebrovascular events and hypertension more often. Subjects with a history of cerebrovascular events were more likely to be receiving statins, based on propensity analysis (P < .001). No further differences were observed. During continuous electrocardiography, 103 subjects (20%) were shown to have a total of 187 ischemic episodes. A decreased incidence of myocardial ischemia was significantly correlated with higher doses of statins and lower low-density lipoprotein (LDL) cholesterol levels, as shown on multivariate (Figures 1 and 2) and univariate (Table) analysis. After adjusting for baseline cholesterol levels (Table), higher statin doses continued to be significantly associated with a decreased incidence of perioperative myocardial ischemia.

Table. Statin therapy in relation to perioperative ischemia and troponin T release, and perioperative and

late cardiac outcome in patients undergoing major vascular surgery.Click on table image for larger version.

The lowest incidence of myocardial ischemia and troponin T release in the perioperative period was observed in subjects with statin doses of more than 50% of the maximum recommended therapeutic dose. The incidence of myocardial ischemia and troponin T release in the perioperative period was lowest in subjects with baseline LDL cholesterol levels < 80 mg/dL (Figure 2). Troponin T release was detected in 83 subjects (23%). Higher statin doses and lower LDL cholesterol levels were shown to be significantly associated with a decreased incidence of troponin T release on multivariate (Table) and univariate (Figures 1 and 2) analysis. Regardless of LDL cholesterol levels, higher statin doses remained significantly associated with a decreased incidence of troponin T release.

One percent of subjects had nonfatal Q-wave MI, and 3% experienced perioperative death; 5% of subjects had nonfatal MI, and late cardiac death occurred in 13% of subjects. Side effects were responsible for discontinuation of statins in 2 subjects (nausea and/or diarrhea in 1 subject and myopathy in 1 subject) during the follow-up period. A decreased incidence of 30-day and late cardiac events was shown to be associated with higher statin doses and decreased LDL cholesterol levels on multivariate analysis (Table). After adjusting for absolute baseline cholesterol levels, higher statin doses remained significantly associated with lower 30-day and late cardiac events.

Discussion

A decreased incidence of perioperative myocardial ischemia and troponin T release, as well as 30-day and late cardiac events, was shown to be significantly associated with higher statin doses and lower LDL cholesterol levels. Regardless of absolute cholesterol levels, higher statin doses continued to be associated with better cardiac outcome. These findings indicate that statins have beneficial cardiovascular effects at subclinical and clinical levels, and should be considered for all major vascular surgery patients.

Perioperative myocardial ischemia may occur from either a reduced supply of oxygen or increased myocardial oxygen demand. Coronary artery plaque rupture, hypoxia, anemia, vasospasm, and hypotension are chief causes of reduced oxygen supply. The use of sympathomimetic drugs, an interruption in alpha blocker treatment, postoperative pain, hypertension resulting from surgical stress, and tachycardia are chief causes of increased oxygen demand. In animal studies, a decrease in the extent of inflammatory cell accumulation in the ischemic myocardium, improved myocardial viability, and preserved coronary blood flow, which was attributed to an increase in the bioavailability of nitric oxide and to a reduction in adhesion molecule expression of the endothelium, have been shown with the administration of statins before induction of myocardial ischemia.⁵ Findings from our study support the idea that pleiotropic effects, such as endothelial function improvement and an increase in nitric oxide resulting in preservation of coronary blood flow, as well as decreased cholesterol levels, reduce myocardial ischemia.⁶

Statin therapy has been shown to decrease cardiovascular morbidity and mortality in large studies of high-risk patients.^7-10 It has also been shown to decrease perioperative cardiovascular events in patients undergoing vascular surgery.^1-3 Atherosclerotic plaque stabilization may be responsible for the decrease in acute thrombotic events shown with statin therapy. As shown in A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID), higher statin doses can significantly decrease atherosclerosis.¹¹ Studies have shown that statins increase tissue inhibitor of metalloproteinase-1 and collagen and decrease cell death, matrix metalloproteinase-2, inflammation, lipid oxidation, and lipids in human carotid plaques.⁴ Our study showed that a 13% decreased risk of perioperative cardiac events occurred with every 10-mg/dL decrease in baseline LDL cholesterol. In addition, a continued beneficial effect of intensive statin therapy and decreased LDL cholesterol levels was seen for late cardiac events.

Only 52% of the subjects in our study were shown to be receiving statins. This indicates that further research documenting the benefit of statin treatment in patients undergoing major vascular surgery is needed, as well as increased awareness among physicians. The American College of Cardiology/American Heart Association guidelines do not recommend beginning statin therapy prior to surgery because the beneficial effects of statins shown in observational studies have not yet been documented in large randomized clinical studies.¹² Among patients undergoing major vascular surgery, coronary atherosclerosis is common, with 92% of patients showing coronary abnormalities on coronary angiography.¹³ The risk of perioperative events is increased with surgery.¹⁴ Decreasing LDL cholesterol levels to < 100 mg/dL in patients with the risk equivalents of coronary artery disease based on the National Cholesterol Education Program Adult Treatment Panel III guidelines should be extended to patients undergoing major vascular surgery.¹⁵ Further risk reduction can be achieved with LDL cholesterol levels < 80 mg/dL, as shown in the current study.

There were several limitations of our study. The statin drugs were not randomly assigned; however, there were no significant differences in cardioprotective drugs and demographic characteristics between those receiving and those not receiving statins. Possible confounding factors were adjusted using propensity scores and multivariate analysis. The results may not be generalizable to patients undergoing general or low-risk surgery, as the results apply to those undergoing major noncardiac vascular surgery. Furthermore, 0.03 ng/mL was used as the cutoff level for troponin T levels because lower troponin T levels do not meet the imprecision criteria (coefficient of variation) of < 10%.

Conclusions

We evaluated whether intensive statin therapy and lower LDL cholesterol levels were associated with improved cardiac outcomes in vascular surgery subjects. Higher statin doses and decreased LDL cholesterol level were associated with lower perioperative myocardial ischemia, perioperative troponin T release, and 30-day and late cardiac events in major vascular surgery. Higher doses of statins were associated with better cardiac outcome, even after adjusting for LDL cholesterol levels.