There is evidence that high-dose statin loading before percutaneous coronary revascularization improves outcomes in patients receiving long-term statins. Therefore, the aim of a recent study was to analyze the effects of such additional statin therapy before surgical revascularization.
Coronary artery bypass grafting (CABG) for the treatment of coronary artery disease (CAD) remains one of the most commonly performed operations in Western countries [2]. Large CABG studies show an early mortality rate of about 2%, and even more patients suffer serious complications such as heart attack or stroke, which are associated with higher mortality [3–6]. Oxidative stress resulting from ischemia-reperfusion injury and inflammation contribute to surgical mortality and morbidity [7]. Statins are thought to have a lipid-independent, cardioprotective effect [8,9], which may reduce some of the adverse effects associated with CABG [10–12]. The clinical relevance of pleiotropic statin action has recently been questioned by the STICS trial, which failed to demonstrate a clinical effect of peri-operative statin loading therapy in patients undergoing cardiac surgery [13]. On the basis of this evidence, current guidelines do not recommend statin uptitration before cardiac surgery in patients not taking statins [14].
However, nowadays more than 80% of patients with CHD referred for CABG are already taking statins before surgery, and the effect of additional statin dosing in these patients before surgery is uncertain [15]. Promising evidence from experimental studies [16,17] and the ARMYDA-RECAPTURE study. [18,19] suggest that statin-mediated cardioprotective effects exerted through the PI3K/Akt pathway diminish over time but can be reactivated by high-dose statin loading therapy administered just before a planned and reversible myocardial ischemia-reperfusion sequence, as often occurs in patients undergoing percutaneous coronary intervention (PCI) or CABG. To investigate the efficacy of additional statin loading therapy on clinical outcomes in patients undergoing CABG, the StaRT-CABG (Statin Recapture Therapy before Coronary Artery Bypass Grafting) trialwas designed [1].
Statin loading therapy or placebo
Eligible patients had to be at least 18 years of age, require isolated on- or off-pump CABG for a cardiovascular disorder, and already be taking a statin for at least 30 days before surgery with one of the four statins most commonly prescribed in Germany (simvastatin, atorvastatin, pravastatin, and fluvastatin). Major exclusion criteria included concomitant cardiovascular surgery for CABG, acute coronary syndrome (ACS) with ST-segment elevation or ACS without ST-segment elevation with cardiogenic shock, disease requiring immediate CABG within 24 hours of hospital admission, history of atrial fibrillation, or renal (serum creatinine >2 mg/dl or dialysis) or liver disease.
Patients admitted to the hospital for CABG were randomly assigned to receive either a statin or placebo in two separate doses before surgery [20]. Randomization was performed using a Web-based system with permuted blocks of different lengths stratified by statin and study center. Patients in both treatment groups received their regular statin until the day before surgery. In the statin group, patients received an additional statin dose 12 hours before CABG, which was topped up to the maximum daily dose of the prescribed statin. Statin loading therapy was based on the recommended maximum oral daily dose: 80 mg/day for simvastatin, atorvastatin, or fluvastatin, respectively, and 40 mg/day for pravastatin. Two hours before surgery, patients again received the maximum statin dose. In the placebo group, placebo tablets were administered 12 and two hours before surgery and were matched regardless of the statin used.
All-cause mortality, myocardial infarction, and acerebrovascular event.
The primary end point was a serious adverse cardiac and cerebrovascular event (MACCE) within 30 days of surgery, defined as a combination of all-cause mortality, MI, stroke, or transient ischemic attack (TIA). MI was defined according to the third universal definition [21]. Type 5 MI according to CABG was defined as peak troponin T >10 times the upper limit of normal (ULN) with at least one of the following criteria: (i) new pathological Q waves; (ii) new left bundle branch block; (iii) angiographically documented new graft or new native coronary artery occlusion; (iv) imaging evidence of new regional wall motion abnormalities. Late MI was diagnosed when there was a new elevation of troponin T from a previous nadir to above ULN with at least one of the following criteria: (i) pathological Q waves (Q wave MI) or (ii) ST-segment elevation.
Secondary end points included the occurrence of serious adverse cardiac events (MACE), defined as death from cardiac causes and MI, myocardial infarction, repeat revascularization within 30 days of surgery, atrial fibrillation, length of hospital and ICU stay, and all-cause mortality within 12 months of CABG.
Patients on long-term statin treatment (≥30 days).
A total of 2635 patients were enrolled in the study; 1320 patients were randomly assigned to the statin group and 1315 patients to the placebo group. After randomization and according to protocol, 117 patients in the statin group and 112 patients in the placebo group were excluded from the modified intention-to-treat study. This resulted in a total number of 2406 patients and 1203 patients per group. Baseline demographics were balanced between groups except for age and presence of left main stem disease, both of which were higher in the placebo group. The mean age of patients was 66±9 years, 358 (14.9%) were women, 836 (34.7%) had diabetes, 1892 patients (78.6%) had three-vessel disease, and most patients (n=2162; 89.9%) were scheduled for elective CABG. The mean logistic EuroSCORE was 2.1 (IQR 1.3-3.4). Statin type and dose were evenly distributed among groups, with most patients taking simvastatin (n=1562; 64.9%), followed by atorvastatin (n=746; 31.0%). Treatment compliance (i.e., taking both doses prescribed in the protocol) was achieved in 2292 of 2406 (95.3%) patients.
Primary endpoint and MACCE components
The primary outcome (MACCE) occurred at 30 days in 167 (13.9%) of 1203 patients in the statin group compared with 179 (14.9%) of 1203 patients in the placebo group (OR 0.93; 95% CI 0.74-1.18; p=0.562). At 30 days, there were no statistically significant differences between groups in the incidence of each MACCE component: Death in 29 patients (1.2%), MI in 301 (12.5%), and a cerebrovascular event (stroke or TIA) in 39 patients (1.6%). Stroke as part of the composite endpoint of cerebrovascular events occurred more frequently in the statin group than in the placebo group (OR 2.24; 95% CI 1.02-4.91; p=0.045). Statin-loading therapy did not significantly affect the incidence of the primary endpoint in any of the predefined subgroups (Fig. 1) [1]. Per-protocol analysis and an exploratory intention-to-treat analysis treating missing data for the primary end point as an event yielded similar results except for a statistically nonsignificant difference between groups for stroke.
Secondary results
MACE at 30 days occurred in 146 (12.1%) of 1203 patients in the statin group compared with 163 (13.5%) of 1203 patients in the placebo group (OR 0.88; 95% CI 0.69-1.12; p=0.300). In addition, statin treatment had no significant effect on the rate of repeat revascularization at 30 days, postoperative atrial fibrillation, or length of hospital and intensive care unit stay. For perioperative myocardial injury, 93.7% (9013 of 9624) of all scheduled troponin T measurements were available. Statin therapy had no relevant effect on the troponin T release curve (Fig. 2) [1]. Follow-up at 12 months was 99.4% complete (2391 of 2406 patients). There was no difference in all-cause mortality at 12 months (hazard ratio 1.05; 95% CI 0.66-1.67; p=0.825), which occurred in 37 (3.1%) of 1198 patients assigned to statin loading therapy compared with 35 (2.9%) of 1193 in the placebo group.
Safety results
Safety outcomes were closely monitored, and there were no statistically significant differences between treatment groups. No adverse muscle effects were observed in the statin group. There were no differences in other inpatient outcomes after CABG. A higher CK release curve was observed in the statin group compared to placebo (CK +4.6%, 95% CI -1.9%-11.6%; p=0.025). The incidence of adverse events was comparable in both treatment groups.
Statin “booster” before bypass surgery without protective effect
In light of the available evidence from the STICS trial, which showed no beneficial clinical effects of preoperative statin loading in predominantly statin-naive CABG patients, the results of the StaRT-CABG trial also do not support the routine use of additional statin treatment in patients already taking statins before isolated elective CABG [13].
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