Statin pretreatment has been reported to have a cardioprotective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI are still controversial. We prospectively evaluated the effect of long-term statin therapy on infarct size (IS), myocardial salvage index (MSI), and microvascular obstruction (MVO) in consecutive patients with STEMI who underwent primary PCI. Two-hundred thirty patients with STEMI (mean age 61 ± 11 years, 183 men) who underwent primary PCI were evaluated with cardiac magnetic resonance (CMR) imaging during hospitalization (median 4 days after primary PCI). In all patients, we measured peak troponin I level, whereas IS, MSI, and MVO were determined by CMR. Fifty patients (22%) were on long-term statin therapy and showed a significantly lower troponin I peak value compared to patients without previous statins (54 ± 47 vs 88 ± 106 ng/ml; p = 0.02). At CMR evaluation, IS related to the index event was significantly smaller (12.5 ± 11.5 vs 18.5 ± 18.5 g, p = 0.05), and MSI was higher (0.68 ± 0.25 vs 0.52 ± 0.30; p <0.01) in patients with previous statin therapy. MVO was also less frequent (10% vs 20%; p = 0.14) in this group. At multivariate analysis, previous statin therapy remained significantly associated with IS and MSI (p = 0.05 and 0.02, respectively). In conclusion, this study suggests that long-term statin therapy before primary PCI in patients with STEMI is associated with smaller IS and higher MSI. Future studies are warranted to confirm these findings and to investigate potential clinical implications.
In patients with ST-elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (pPCI) increases salvage of viable myocardium and reduces infarct size (IS). The process of restoring blood flow to the ischemic myocardium, however, can induce additional endothelial and myocardial damage (reperfusion injury), that negatively impacts on IS and on cardiac morbidity and mortality rates. Therefore, further cardioprotective strategies aimed at minimizing reperfusion injury are still a critical need in patients with STEMI undergoing pPCI. Pretreatment with statins in patients with stable angina or non–ST-elevation acute coronary syndromes undergoing elective or urgent PCI, respectively, has been shown to reduce myocardial injury and to improve clinical outcomes, possibly due to the pleiotropic properties of these drugs. Conversely, data on a cardioprotective effect of statin pretreatment in patients with STEMI undergoing pPCI are more controversial. Although previous studies demonstrated a reduction of IS after reperfusion in animal models of myocardial infarction pretreated with statins, these results could not be consistently reproduced in patients with STEMI. The comparison of IS in patients with STEMI undergoing pPCI with or without statin therapy before hospitalization represents a good opportunity to explore the role of pretreatment with these drugs in this clinical setting. In this prospective study, we evaluated IS, myocardial salvage index (MSI), and microvascular obstruction (MVO) by cardiac magnetic resonance (CMR) imaging in a consecutive cohort of patients with STEMI who underwent pPCI comparing patients on long-term statin with those without previous therapy.
Methods
This prospective, single-center study was conducted at the Centro Cardiologico Monzino from January 14, 2012, to January 31, 2015. We enrolled all consecutive patients with STEMI who underwent pPCI. Patients were included if they presented within 12 hours (18 hours for STEMI complicated by cardiogenic shock) from symptom onset. Patients undergoing cardiac surgery for emergency coronary revascularization and/or mechanical complications, those dying during pPCI or during coronary care unit (CCU) stay, those with contraindications to CMR, and those with uncertain statin compliance were excluded from the study. The study was approved by the institutional review board of our Institute, and informed consent was obtained from all participants. No extramural funding was used to support this work.
Primary PCI was performed by a 24-hour on-call interventional team, according to standard clinical practice. Patients were interviewed at admission on type, dose, duration of, and compliance to statin prescription before the index event. Demographic, clinical, biochemical, echocardiographic, and angiographic data were also obtained. Left ventricular ejection fraction was measured by echocardiogram in all patients within 24 hours from hospital admission. All angiographic analyses were carried out by 2 independent observers (SC and VM). The Thrombolysis In Myocardial Infarction (TIMI) flow grade before and after pPCI was evaluated by a standard method. The primary end points of the study were IS and MSI, as assessed by CMR imaging, in reperfused patients with STEMI with and without previous statin therapy. The secondary end point was troponin I peak value in the 2 groups.
CMR studies were performed with 1.5T unit (Discovery MR450; GE Healthcare, Milwaukee, Wisconsin), using a dedicated cardiac software, phased-array surface receiver coil, and electrocardiogram triggering. Breath-hold steady-state free-precession cine CMR was performed in vertical and horizontal long-axis and short-axis orientations to measure left and right end-diastolic volumes and ejection fractions. Breath-hold black-blood T2-weighted short inversion-time inversion-recovery fast spin-echo (T2-weighted imaging) was performed with the same prescription of cine CMR images. Myocardium with a signal intensity >2 SD above mean signal intensity of remote noninfarcted myocardium was considered area at risk, and it was measured as absolute mass or as percentage of entire left ventricle mass. Breath-hold contrast-enhanced segmented T1-weighted inversion-recovery gradient-echo sequence (late-gadolinium enhancement [LGE] imaging) was performed to estimate IS, 10 to 20 minutes after an intravenous bolus of 0.1-mmol/kg Gadolinium-BOPTA (Multihance-Bracco, Milan, Italy), with an inversion time individually adapted to nullify the signal of remote myocardium (usual range 220 to 300 ms). On postcontrast imaging, LGE was considered present if signal intensity of the hyperenhanced myocardium was >5 SD above the mean signal intensity of remote myocardium. MVO was defined as a hypoenhanced region within the infarcted myocardium. When present, MVO was included in the hyperintense myocardium for LGE quantification. Left ventricular LGE was expressed as an absolute value (grams). Myocardial salvage index was calculated as the ratio between area at risk (grams) minus IS (grams) and area at risk (grams). In patients with previous myocardial infarction, we also measured, when possible, the IS because of the index event only. All CMR studies were analyzed offline by the consensus of 2 experienced observers (GP, SC).
A sample size of 224 patients was calculated under the assumption of a 20% difference in mean MSI between the 2 groups (patients with vs those without previous statin therapy). This sample size allowed 90% statistical power to deem as significant (α error of 0.05). Continuous variables are presented as mean ± SD, and they were compared using the t test for independent samples. Variables not normally distributed are presented as median and interquartile ranges and compared with the Wilcoxon rank sum test. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate. Pearson correlation was used to detect possible correlations between IS and MSI and statin dose and length of treatment. Differences in IS among low-density lipoprotein (LDL) cholesterol quartiles were assessed by analysis of variance for continuous variables. Multiple linear regression analysis was used to adjust for potential confounders. The variables included in the model were selected according to the so-called epidemiologic approach, by including those recognized to potentially influence IS and MSI (age, diabetes mellitus, anterior STEMI, previous aspirin, and previous β- blockers). All tests were 2 sided, and a p value <0.05 was required for statistical significance. All calculations were computed with SAS software package version 9.4 (SAS Institute Inc., Cary, North Carolina).
Results
Three-hundred fifty-five patients with STEMI treated with pPCI were initially screened, and 230 of them (mean age 61 ± 11 years, 183 men), who underwent CMR before hospital discharge (median 4 days, interquartile range 3 to 6), were included in this study. In all patients, information on previous statin therapy was available. In particular, 50 patients (22%) were on long-term statin therapy with atorvastatin in 23 cases (46%), simvastatin in 15 (30%), pravastatin in 1 (2%), and rosuvastatin in 11 (22%). The average statin dose was 22 ± 10 mg/day (equivalent dose 28 ± 20 mg/day), and the duration of statin treatment before the index event was 5 ± 3.5 years (>6 months in all patients).
Table 1 reports the clinical characteristics of the patient groups according to whether they were on previous statin therapy or not. Notably, total and LDL cholesterol levels at hospital admission were significantly lower in the statin group, confirming the overall compliance to statin therapy.
| Variable | Prior Statin Therapy | P value | |
|---|---|---|---|
| Yes (n=50) | No (n=180) | ||
| Age (years) | 63±10 | 60±11 | 0.07 |
| Men | 42 (84%) | 141 (78%) | 0.37 |
| Body weight (kg) | 76±12 | 77±13 | 0.36 |
| Height (cm) | 168±7 | 170±8 | 0.15 |
| Body mass index (kg/m 2 ) | 27±4 | 27±4 | 0.92 |
| Diabetes mellitus | 11 (22%) | 15 (8%) | 0.006 |
| Hypertension | 29 (58%) | 77 (43%) | 0.06 |
| Smoker | 32 (64%) | 111 (62%) | 0.76 |
| Prior myocardial infarction | 19 (38%) | 7 (4%) | <0.001 |
| Prior coronary bypass | 8 (16%) | 0 | <0.001 ∗ |
| Prior PCI | 21 (42%) | 9 (5%) | <0.001 |
| Time-to-treatment (hours) | 5.1±5.4 | 6.4±9.2 | 0.36 |
| Thienopyridine pre-loading | 50 (100%) | 180 (100%) | 1.0 |
| Infarct related coronary artery | |||
| Left anterior descending | 19 (38%) | 83 (46%) | 0.02 ∗ |
| Right | 19 (38%) | 65 (36%) | |
| Left circumflex | 8 (16%) | 31 (17%) | |
| Bypass graft | 4 (8%) | 0 (0%) | |
| Left main | 0 | 1 (0.5%) | |
| TIMI flow before PCI | |||
| 0 | 50 (100%) | 175 (97%) | 0.58 ∗ |
| I | 0 | 5 (3%) | |
| TIMI flow after PCI | |||
| 0 | 0 | 1 (0.5%) | 1.0 ∗ |
| I | 0 | 0 | |
| II | 0 | 3 (2%) | |
| III | 50 (100%) | 176 (98%) | |
| LVEF (%) | 50±11 | 49±12 | 0.82 |
| Medication before hospital admission | |||
| Aspirin | 32 (64%) | 66 (37%) | <0.001 |
| Beta-blockers | 18 (36%) | 19 (11%) | <0.001 |
| ACE/AR blockers | 20 (40%) | 47 (23%) | 0.06 |
| Warfarin | 1 (2%) | 1 (0.5%) | 0.38 ∗ |
| Medication during CCU stay | |||
| Aspirin | 49 (98%) | 177 (98%) | 1.0 ∗ |
| Ticlopidine | 2 (4%) | 3 (2%) | 0.20 ∗ |
| Clopidogrel | 11 (22%) | 50 (28%) | |
| Prasugrel | 22 (44%) | 93 (52%) | |
| Ticagrelor | 15 (30%) | 34 (19%) | |
| Statin | 50 (100%) | 173 (96%) | 1.0 |
| Beta-blockers | 44 (88%) | 140 (78%) | 0.29 |
| ACE/AR blockers | 32 (64%) | 129 (72%) | 0.29 |
| Laboratory values at hospital admission | |||
| Blood glucose (mg/dl) | 146 (114;158) | 134 (117;153) | 0.26 † |
| Serum creatinine (mg/dl) | 0.95±0.3 | 0.91±0.2 | 0.24 |
| eGFR (ml/min/1.73m 2 ) | 86 (67;103) | 88 (76;104) | 0.41 † |
| Hemoglobin (g/dl) | 14.3±1.4 | 14.3±1.4 | 0.88 |
| Hemoglobin A1c (mmol/mol) | 46.5±18 | 40.4±8 | <0.001 |
| Troponin I (ng/ml) | 0.95 (0.04;6.7) | 0.81 (0.14; 6.7) | 0.36 † |
| Total cholesterol (mg/dl) | 170 (145;193) | 193 (168;220) | <0.001 † |
| HDL (mg/dl) | 43 (36;51) | 40 (34;46) | 0.30 |
| LDL (mg/dl) | 106 (78;123) | 127 (102;149) | <0.001 † |
| Triglycerides (mg/dl) | 107 (77;149) | 110 (74;154) | 0.95 † |
| hs-CRP (mg/dl) | 3.04±2.86 | 8.53±4.37 | 0.008 |
| CCU length of stay (days) | 4.0±1.0 | 4.2±1.4 | 0.54 |
Patients on long-term statin therapy showed an almost 40% lower troponin I peak value during hospitalization, compared to patients without previous statin therapy ( Figure 1 ). Table 2 reports the incidence of major clinical complications during CCU stay in the 2 groups.
| Variable | Prior Statin Therapy | P value ∗ | |
|---|---|---|---|
| Yes (n=50) | No (n=180) | ||
| Mortality | 0 | 0 | 1.0 |
| CPR, VT, or VF | 5 (10%) | 20 (11%) | 0.82 |
| Atrial fibrillation | 4 (8%) | 14 (8%) | 0.95 |
| High-degree conduction disturbances requiring PM | 4 (8%) | 5 (3%) | 0.11 |
| Acute pulmonary edema | 2 (4%) | 8 (4%) | 1.0 |
| Respiratory failure requiring MV | 0 | 1 (0.6%) | 1.0 |
| Cardiogenic shock requiring IABP | 2 (4%) | 7 (4%) | 1.0 |
| Major bleeding requiring blood transfusion | 0 | 1 (0.6%) | 1.0 |
| Acute kidney injury (Stage ≥1 AKIN) | 4 (8%) | 12 (7%) | 0.75 |
At CMR evaluation, there were no significant differences in left ventricular ejection fraction, area at risk, IS, and MSI between the 2 patient groups ( Table 3 and Figure 2 ). Given that a significantly higher rate of previous myocardial infarction was present (38% vs 4%) in patients on long-term statin therapy, when only the IS related to the index event was considered, a 32% smaller IS and a 24% higher MSI were found in the statin group, compared to those without previous statin therapy ( Figure 3 ).
| Variable | Prior Statin Therapy | P value | |
|---|---|---|---|
| Yes (n=50) | No (n=180) | ||
| Heart rate (bpm) | 64±10 | 68±12 | 0.04 |
| Left ventricular end-diastolic volume (mL) | 80 (69;89) | 82 (71;93) | 0.40 ∗ |
| Left ventricular end-systolic volume (mL) | 38 (30;51) | 42 (32;54) | 0.14 ∗ |
| Left ventricular ejection fraction (%) | 49±11 | 49±11 | 0.82 |
| Left ventricular mass (grams) | 107 (88;143) | 119 (91;137) | 0.68 ∗ |
| Right ventricular end-diastolic volume (mL) | 68±17 | 67±21 | 0.82 |
| Right ventricular end-systolic volume (mL) | 27±9 | 26±11 | 0.76 |
| Right ventricular ejection fraction (%) | 61±10 | 59±8 | 0.23 |
| Area at risk (grams) | 32±27 | 35±24 | 0.47 |
| Area at risk/left ventricular mass (%) | 28±13 | 30±15 | 0.51 |
| Infarct size/left ventricular mass (%) | 18±10 | 16±9 | 0.30 |
| Micro-vascular obstruction | 5 (10%) | 36 (20%) | 0.14 |
