Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III - DECREASE III

Sep 08, 2009
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Trial Sponsor:
Supported by Novartis, the Netherlands Organization for Health Research and Development, Erasmus Medical Center, Stichting Lijfen Leven, and the Netherlands Heart Foundation
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
09/08/2009
Original Posted Date:
09/08/2009
References

Description:

The goal of this trial was to assess whether the introduction of perioperative statin therapy with fluvastatin XL, in addition to beta-blockers, is associated with a decrease in myocardial ischemic events in patients undergoing noncardiac vascular surgery.

Hypothesis:

Fluvastatin XL would be associated with a decreased incidence of ischemic events in high-risk patients undergoing noncardiac surgery, compared with placebo.

Study Design

Study Design:

Patients Screened: 1,669
Patients Enrolled: 497
Mean Follow Up: 30 days
Mean Patient Age: 65.9 years (median)
Female: 25

Patient Populations:

  • Age >40 years
  • Scheduled for either abdominal aortic aneurysm repair, abdominal aortic stenosis surgery, lower limb arterial reconstruction, or carotid artery stenosis repair
  • At least 51 points on the prespecified Erasmus MC risk index (an estimated risk of cardiovascular death of more than 2%)

Exclusions:

  • Current statin therapy
  • Contraindication to statin therapy
  • Surgery that interferes with continuous 12-lead ECG recording, such as thoracic and upper abdominal surgery
  • Emergency surgery
  • Unstable coronary artery disease
  • Extensive stress-induced myocardial ischemia
  • Previous participation in this study
  • Reoperation within 30 days of an initial surgical procedure

Primary Endpoints:

Myocardial ischemia within 30 days postoperatively, determined by electrocardiogram (ECG) and/or troponin release

Secondary Endpoints:

  • Efficacy: Composite rate of cardiovascular death and nonfatal MI
  • Safety: CK elevations, elevations in AST/ALT, myopathy, and rhabdomyolysis
  • Change in levels of biomarkers including lipids, high-sensitivity C-reactive protein, and interleukin-6

Drug/Procedures Used:

Fluvastatin XL 80 mg daily, for a median of 37 days prior to surgery, and continued for at least 1 month after, or matching placebo

Concomitant Medications:

Beta-blockers (100%), antiplatelet agents (61.6%), angiotensin-converting enzyme inhibitors (27.2%), angiotensin-receptor blockers (15.5%)

Principal Findings:

A total of 497 patients, who had never been on statins before, were randomized over a period of 4 years. About 28% had a history of prior myocardial infarction (MI), 20% had diabetes, and 28% had a history of stroke. Baseline low-density lipoprotein cholesterol (LDL-C) was about 129 mg/dl. The median Erasmus MC risk index for surgery was 56 points. The majority of patients underwent either abdominal aortic procedure (48%) or lower limb arterial reconstructions (39%).

As expected, there was a significant reduction in total cholesterol (20.0% vs. 3.9%, p < 0.001), LDL-C (24.1% vs. 3.1%, p < 0.001), but not high-density lipoprotein cholesterol (1.2% vs. 1.3%, p = 0.20) in the fluvastatin XL arm, compared with placebo, respectively. Myocardial ischemia within 30 days was significantly lower in the fluvastatin XL arm compared with placebo (10.8% vs. 19.0%, hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.34-0.88, p = 0.01). The number needed to treat analysis demonstrated that only 12 patients needed to be treated with fluvastatin XL to prevent one excess MI. The combined endpoint of cardiovascular mortality or nonfatal MI was significantly lower in the fluvastatin XL arm as well (4.8% vs. 10.1%, HR 0.47; 95% CI 0.24-0.94, p = 0.03). There was no difference between the two arms in the incidence of all-cause mortality (2.4% vs. 4.9%, p = 0.14). At a median of 37 days after admission, % decrease in inflammatory markers such as high-sensitivity C-reactive protein (20.5% vs. -3.3%, p ≤ 0.001) and interleukin-6 (32.7% vs. 4.2%, p < 0.001) was also significantly reduced in the fluvastatin XL arm compared with placebo.

The incidence of adverse events, including those experiencing a rise in creatine kinase (CK) >10 × upper limit of normal (ULN), was similar between the two groups (4.0% vs. 3.2, p = 0.81), as was the incidence of alanine aminotransferase (ALT) elevation >3 × ULN (3.2% vs. 5.3%, p = 0.27). There were no episodes of myopathy or rhabdomyolysis in either arm.

Interpretation:

The introduction of perioperative statin therapy with fluvastatin XL in high-risk patients undergoing elective noncardiac vascular surgery is associated with a significant reduction in ischemic endpoints, compared with placebo. There was no increase in the incidence of adverse effects. Although they excluded patients already on statins, at least a quarter of the patients in the study had either a history of MI or a cerebrovascular accident, who should have been on statins to begin with, given the abundant data on the efficacy of statins for secondary prevention in this patient population. It is unknown if these patients were the ones who predominantly benefited by the use of statins in the perioperative period. Moreover, although these short-term data appear promising, long-term follow-up data are also awaited.

It is unlikely that these results are specific for fluvastatin alone and, thus, probably represent a class effect of statins in the perioperative period. The results of this study add to a growing body of literature that seems to suggest a beneficial effect of perioperative statin therapy in patients undergoing noncardiac surgery. This and other studies seem to suggest that this effect may at least in part be mediated by a reduction in the inflammatory milieu that accompanies surgical procedures.

References:

Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-9.

Fluvastatin XL Use Is Associated With Improved Cardiac Outcome After Major Vascular Surgery. Results From a Randomized Placebo-Controlled Trial: DECREASE III. Presented by Dr. Don Poldermans at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Creatine Kinase, Cholesterol, LDL, Interleukin-6, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Fatty Acids, Monounsaturated, Perioperative Period, Rhabdomyolysis, Lipoproteins, LDL, C-Reactive Protein, Indoles, Cholesterol, HDL, Confidence Intervals, Lipoproteins, HDL, Carotid Stenosis, Aortic Aneurysm, Abdominal, Diabetes Mellitus


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