Statins have many favorable pleiotropic effects beyond their lipid-lowering properties. The aim of this study was to evaluate the impact of long-term statin pretreatment on the level of systemic inflammation and myocardial perfusion in patients with acute myocardial infarctions. This was a retrospective study of 1,617 patients with acute ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention <12 hours after the onset of symptoms. Angiographic no-reflow was defined as postprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade ≤2. Long-term statin pretreatment was significantly less common in the no-reflow group (6.2% vs 21%, p <0.001). The serum lipid profiles of the groups were similar (p >0.05 for all parameters). Baseline C-reactive protein levels (10 ± 8.2 vs 15 ± 14 mg/L, p <0.001) and the frequency of angiographic no-reflow (3.9% vs 14%, p <0.001) were significantly lower, and myocardial blush grade 3 was more common (50% vs 40%, p = 0.006) in the statin pretreatment group (n = 306). Moreover, the frequency of complete ST-segment resolution (>70%) (70% vs 59%, p <0.001) and the left ventricular ejection fraction were higher (49 ± 7.5% vs 46 ± 8.3%, p <0.001) and peak creatine kinase-MB was lower (186 ± 134 vs 241 ± 187 IU/L, p <0.001) in the statin-treated group. In conclusion, long-term statin pretreatment is associated with lower C-reactive protein levels on admission and better myocardial perfusion after primary percutaneous coronary intervention, leading to lower enzymatic infarct area and a more preserved left ventricular ejection fraction. This is a group effect independent of lipid-lowering properties.
Statins are commonly used in the primary and secondary prophylaxis of atherosclerotic cardiovascular diseases and are associated with lower mortality rates. They also cause a significant decrease in cardiovascular mortality when initiated early in acute coronary syndromes. In addition to lipid-lowering properties, statins have been demonstrated to have pleiotropic effects, such as improvement of endothelial function, anti-inflammatory, and anticoagulant and antioxidant effects. A recent meta-analysis reported that statin pretreatment reduced periprocedural myonecrosis in elective percutaneous coronary intervention (PCI). There have been only a few trials, with low patient volumes, reporting that statin pretreatment was associated with better myocardial perfusion and a reduction of the no-reflow phenomenon after primary PCI. The aim of this retrospective study was to evaluate the impact of long-term statin pretreatment on the level of systemic inflammation and myocardial perfusion in patients with acute ST-segment elevation myocardial infarctions (STEMIs) who underwent primary PCI.
Methods
The study population consisted of 1,625 patients with acute STEMIs who were admitted to Kartal Kosuyolu Heart Education and Research Hospital and underwent PCI <12 hours after the onset of symptoms from January 2006 to April 2008. The inclusion criteria were (1) typical ongoing ischemic chest pain for >30 minutes and (2) ST elevation ≥1 mm in ≥2 contiguous leads (2 mm for leads V 1 to V 3 ) or new-onset left bundle branch block. Eight patients (0.5%) with saphenous graft intervention were excluded from the study. The remaining 1,617 patients formed the study population. The study was approved by our hospital ethics committee, and all patients gave written informed consent.
Clinical and demographic properties of the patients were recorded from hospital files and computer records. Baseline hemographic parameters and C-reactive protein (CRP), urea, creatinine, glucose, creatine kinase, creatine kinase-MB isoform (CK-MB), and troponin I levels were obtained on admission. Blood samples were repeated for creatine kinase, creatine kinase-MB, and troponin I every 6 hours until peak levels were reached and repeated daily thereafter. Hemographic parameters and urea and creatinine levels were also evaluated every day. CRP was measured by nephelometric method (Beckman Coulter, Dublin, Ireland) with a minimal detectable level of 1 mg/L. Electrocardiography was performed on admission, immediately after the procedure, 60 minutes after the procedure, and daily thereafter. Postprocedural transthoracic echocardiography (Vivid 3 or Vivid 5; GE Vingmed Ultrasound AS, Horten, Norway) was performed during in-hospital period. The left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson’s method.
All patients received chewable aspirin 300 mg and a loading dose of clopidogrel 300 to 600 mg on admission and intravenous standard heparin 70 U/kg before the procedure. The use of a glycoprotein IIb/IIIa inhibitor (tirofiban) was left to the primary operator’s discretion. All primary PCI procedures were performed by experienced interventional cardiologists through a femoral approach using a 7Fr guiding catheter. The lesions were passed by 0.014-inch guidewires. In patients with baseline Thrombolysis In Myocardial Infarction (TIMI) flow grades ≥1, primary angioplasty was performed with or without stenting according to the primary operator’s discretion. After the procedures, all patients were followed up in the coronary intensive care unit until clinical stabilization was established. During the period of hospitalization, all patients were given subcutaneous enoxaparin 1 mg/kg twice daily, acetylsalicylic acid 150 mg/day, and clopidogrel 75 mg/day.
All coronary hemodynamic data were recorded, stored off-line, and analyzed by 2 independent investigators. Coronary lesions were evaluated in ≥2 nonforeshortened angiographic views at the end-diastolic phase. Lesions >50% were labeled as hemodynamically significant. Preprocedural TIMI flow, collateral flow (Rentrop), infarct-related artery, severity of the lesions, and number of diseased vessels were noted. Postprocedural final TIMI flow grade and myocardial blush grade (MBG) were assessed.
Preinfarction angina was defined as cardiac symptoms lasting <30 minutes that occurred <48 hours before the onset of infarction. Reperfusion time denotes the time from the onset of chest pain to the first intracoronary balloon inflation. Cardiogenic shock was defined as persistent systolic blood pressure <90 mm Hg nonresponsive to fluid replacement or the need for inotropes or intra-aortic balloon pumping required to maintain blood pressure >90 mm Hg. Hypercholesterolemia was defined as the presence of a total cholesterol level >200 mg/dl on admission or maintenance of normal levels under statin therapy. Preprocedural grade 2/3 collateral flow was accepted as well-developed collateral flow. No-reflow was defined as the presence of TIMI flow grade ≤2 in the absence of residual stenosis, spasm, dissection, or distal embolization. ST-segment resolution (STR) was calculated as the ratio of the sum of ST-segment elevation on admission minus the sum of ST-segment elevation 60 minutes after primary PCI divided by the sum of ST-segment elevation on admission. STR >70% was defined as successful reperfusion (complete resolution). STR of 30% to 70% was defined as incomplete reperfusion, and STR <30% was defined as absence of reperfusion.
Continuous variables are expressed as mean ± SD. Categorical variables are expressed as percentages. Group means for continuous variables were compared using independent-samples t test or 1-way analysis of variance, as appropriate. Categorical variables were compared using chi-square or Fisher’s exact tests. Multivariate logistic regression analysis was applied to identify the independent predictors of no-reflow phenomenon. All variables showing significance values <0.05 on univariate analysis (age, diabetes mellitus, admission blood glucose level, hypertension, current smoking, statin pretreatment, reperfusion time >4 hours, Killip class ≥2, baseline creatinine, mean platelet volume, preprocedural TIMI flow grade ≤1, stenting, and level of CRP) were included in the model. Two-tailed p values <0.05 were considered to indicate statistical significance. SPSS version 11.5 (SPSS, Inc., Chicago, Illinois) was used in all statistical analysis.
Results
The study population consisted of 1,617 patients with acute STEMIs (81% men, mean age 56 ± 12 years). On admission, 306 of the patients (19%) were receiving long-term statin treatment. Of those, 51% were taking atorvastatin (18 ± 12 mg/day), 15% simvastatin (20 ± 10 mg/day), 9% fluvastatin (61 ± 20 mg/day), 12% rosuvastatin (15 ± 8 mg/day), and 13% pravastatin (20 ± 11 mg/day). Two hundred thirty-two of the patients (76%) were receiving statin therapy for hyperlipidemia, and in 74 patients (24%), statins were initiated for the other indications mentioned in the National Cholesterol Education Program Adult Treatment Panel III guidelines, such as having ≥2 risk factors with 10-year coronary heart disease risk of 10% to 20% and low-density lipoprotein ≥130 mg/dl.
The incidence of angiographic no-reflow was 12%. The mean age was significantly higher in the no-reflow group than in the reflow group (60 ± 12 vs 55 ± 11 years, p <0.001). There were no differences between the groups with respect to hyperlipidemia, family history, previous coronary intervention, previous myocardial infarction, and infarct localization (p >0.05 for all parameters). The frequencies of diabetes (30% vs 22%, p = 0.016) and hypertension (47% vs 39%, p = 0.031) were higher, and active tobacco use was less frequent (44% vs 55%, p = 0.006) in the no-reflow group. Killip class ≥2 (31% vs 14%) and reperfusion time >4 hours (62% vs 25%) were also significantly more common in the no-reflow group (p <0.001 for both parameters). There was no difference between groups with respect to the previous use of other medications, but statin pretreatment was significantly more common in the reflow group (21% vs 6%, p <0.001). Other demographic and clinical properties of the patients are listed in Table 1 .
| Variable | All Patients | No-Reflow (TIMI Flow Grade ≤2) | Reflow (TIMI Flow Grade 3) | p Value |
|---|---|---|---|---|
| (n = 1,617) | (n = 193) | (n = 1,424) | ||
| Age (years) | 56 ± 12 | 60 ± 12 | 55 ± 11 | <0.001 |
| Age ≥65 years | 391 (24%) | 75 (39%) | 316 (22%) | <0.001 |
| Men | 1,315 (81%) | 151 (78%) | 1,164 (82%) | 0.28 |
| Diabetes mellitus | 371 (23%) | 58 (30%) | 313 (22%) | 0.016 |
| Hypertension | 643 (40%) | 91 (47%) | 552 (39%) | 0.031 |
| Dyslipidemia | 636 (39%) | 65 (34%) | 571 (40%) | 0.10 |
| Current smokers | 867 (54%) | 85 (44%) | 782 (55%) | 0.006 |
| Family history | 331 (21%) | 30 (16%) | 301 (20%) | 0.08 |
| AMI history | 89 (5.5%) | 10 (5.2%) | 79 (5.5%) | 0.96 |
| Previous PCI | 122 (7.5%) | 14 (7.3%) | 108 (7.6%) | 0.98 |
| Previous CABG | 43 (2.7%) | 2 (1.0%) | 41 (2.9%) | 0.15 |
| Preinfarction angina | 398 (25%) | 50 (26%) | 348 (24%) | 0.72 |
| Systolic blood pressure (mm Hg) | 133 ± 32 | 136 ± 42 | 132 ± 30 | 0.12 |
| Diastolic blood pressure (mm Hg) | 78 ± 19 | 79 ± 24 | 78 ± 18 | 0.39 |
| Killip class ≥2 | 252 (16%) | 59 (31%) | 193 (14%) | <0.001 |
| Anterior infarct location | 806 (50%) | 108 (56%) | 698 (49%) | 0.08 |
| Reperfusion time (hours) | 3.4 ± 2.0 | 4.8 ± 2.2 | 3.1 ± 1.9 | <0.001 |
| Reperfusion time >4 hours | 481 (30%) | 120 (62%) | 361 (25%) | <0.001 |
| Baseline creatinine (mg/dl) | 0.9 ± 0.5 | 1.1 ± 0.7 | 0.9 ± 0.4 | <0.001 |
| Renal insufficiency ⁎ | 112 (6.9%) | 33 (17%) | 79 (5.5%) | <0.001 |
| Mean platelet volume (fl) | 9.2 ± 1.3 | 9.4 ± 1.3 | 9.2 ± 1.3 | 0.048 |
| CRP (mg/L) | 14 ± 13 | 22 ± 18 | 13 ± 12 | <0.001 |
| Glucose (mg/dl) | 152 ± 81 | 173 ± 112 | 149 ± 76 | <0.001 |
| Total cholesterol (mg/dl) | 179 ± 44 | 177 ± 52 | 180 ± 43 | 0.48 |
| LDL cholesterol (mg/dl) | 115 ± 39 | 112 ± 45 | 115 ± 38 | 0.33 |
| HDL cholesterol (mg/dl) | 38 ± 11 | 38 ± 11 | 37 ± 11 | 0.40 |
| Triglycerides (mg/dl) | 138 ± 97 | 129 ± 109 | 139 ± 95 | 0.21 |
| Previous medication | ||||
| Aspirin | 139 (8.6%) | 13 (6.7%) | 126 (8.8%) | 0.39 |
| Clopidogrel | 28 (1.7%) | 3 (1.6%) | 25 (1.8%) | 1.00 |
| β blockers | 177 (11%) | 19 (9.8%) | 158 (11%) | 0.69 |
| Statins | 306 (19%) | 12 (6.2%) | 294 (21%) | <0.001 |
| ACE inhibitors/ARBs | 333 (21%) | 39 (20%) | 294 (21%) | 0.96 |
| Insulin | 113 (7.0%) | 14 (7.3%) | 99 (7.0%) | 0.99 |
There were no significant differences between the no-reflow and reflow groups with respect to the number of diseased vessels, good collateral flow, infarct-related artery, preprocedural clopidogrel loading dose, and tirofiban use (p >0.05 for all parameters). However, preprocedural TIMI grade 2 or 3 flow (5% vs 26%, p <0.001) and stent implantation (90% vs 95%, p = 0.005) were significantly lower in the no-reflow group. Postprocedural peak creatine kinase-MB was higher (360 ± 220 vs 213 ± 165 IU/L, p <0.001) and LVEF lower (40 ± 8% vs 48 ± 8%, p <0.001) in the no-reflow group. Other angiographic and procedural properties are listed in Table 2 .
| Variable | All Patients | No-Reflow | Reflow | p Value |
|---|---|---|---|---|
| Multivessel disease | 657 (41%) | 78 (40%) | 579 (41%) | 0.94 |
| Infract-related artery | ||||
| Left anterior descending coronary artery | 807 (50%) | 105 (54%) | 702 (49%) | 0.21 |
| Left circumflex coronary artery | 213 (13%) | 27 (14%) | 186 (13%) | 0.80 |
| Right coronary artery | 568 (35%) | 59 (31%) | 509 (36%) | 0.18 |
| Left main coronary artery/intermediate/diagonal | 29 (1.8%) | 2 (1.0%) | 27 (1.9%) | 0.57 |
| Baseline TIMI flow grade | <0.001 | |||
| 0 | 1,131 (70%) | 174 (90%) | 957 (67%) | |
| 1 | 102 (6.3%) | 10 (5.2%) | 92 (6.5%) | |
| 2 | 224 (14%) | 6 (3.1%) | 218 (15%) | |
| 3 | 160 (10%) | 3 (1.6%) | 157 (11%) | |
| Good collateral flow | 86 (5.3%) | 6 (3.1%) | 80 (5.6%) | 0.19 |
| Clopidogrel loading dose (mg) | 0.44 | |||
| 300 | 27 (1.7%) | 5 (2.6%) | 22 (1.5%) | |
| 600 | 1,590 (98%) | 188 (97%) | 1,402 (99%) | |
| Use of tirofiban before procedure | 710 (44%) | 73 (38%) | 637 (45%) | 0.07 |
| Stent type | 0.96 | |||
| Drug eluting | 76 (5.0%) | 8 (4.6%) | 68 (5.0%) | |
| Bare metal | 1,449 (95%) | 165 (95%) | 1,284 (95%) | |
| Use of stents | 1,617 (94%) | 173 (90%) | 1,352 (95%) | 0.005 |
| Balloon angioplasty | 92 (5.7%) | 20 (10%) | 72 (5.1%) | 0.005 |
| Final TIMI flow grade | <0.001 | |||
| 0 | 15 (0.9%) | 15 (7.8%) | 0 (0.0) | |
| 1 | 49 (3.0%) | 49 (25%) | 0 (0.0) | |
| 2 | 129 (8.0%) | 129 (67%) | 0 (0.0) | |
| 3 | 1,424 (88%) | 0 (0.0) | 1,424 (100%) | |
| Peak creatine kinase-MB (IU/L) | 230 ± 179 | 361 ± 220 | 213 ± 165 | <0.001 |
| STR at 60 minutes ⁎ | <0.001 | |||
| None | 144 (9.3%) | 86 (45%) | 58 (4.3%) | |
| Partial | 468 (30%) | 60 (32%) | 408 (30%) | |
| Complete | 931 (60%) | 44 (23%) | 887 (66%) | |
| Postprocedural LVEF (%) † | 47 ± 8.2 | 40 ± 7.6 | 48 ± 7.9 | <0.001 |
There were no significant differences between the no-reflow and reflow groups with respect to the frequency of hypercholesterolemia and the levels of total and low-density lipoprotein cholesterol (p >0.05 for all parameters). Likewise, in the overall population, these parameters were statistically similar in groups with and without statin pretreatment (p >0.05 for all parameters). However, when only patients with hypercholesterolemia were concerned, the low-density lipoprotein cholesterol, total cholesterol, and triglyceride levels of the patients with previous statin use were lower (p <0.001 for all parameters) than in the patients with no statin therapy, and high-density lipoprotein levels were similar ( Table 3 ).
| Variable | All Patients | p Value | Patients With Hypercholesterolemia | p Value | ||
|---|---|---|---|---|---|---|
| Statin | No Statin | Statin | No Statin | |||
| Total cholesterol (mg/dl) | 176 ± 55 | 180 ± 41 | 0.13 | 188 ± 55 | 216 ± 40 | <0.001 |
| LDL cholesterol (mg/dl) | 112 ± 48 | 116 ± 36 | 0.10 | 122 ± 48 | 141 ± 41 | <0.001 |
| HDL cholesterol (mg/dl) | 38 ± 12 | 37 ± 11 | 0.78 | 38 ± 12 | 38 ± 11 | 0.83 |
| Triglycerides (mg/dl) | 135 ± 93 | 139 ± 98 | 0.49 | 148 ± 101 | 198 ± 134 | <0.001 |
| Systolic blood pressure (mm Hg) | 135 ± 32 | 132 ± 32 | 0.10 | 135 ± 31 | 134 ± 33 | 0.73 |
| Diastolic blood pressure (mm Hg) | 81 ± 19 | 77 ± 19 | 0.001 | 81 ± 18 | 77 ± 20 | 0.027 |
| Glucose (mg/dl) | 155 ± 79 | 152 ± 82 | 0.54 | 150 ± 72 | 161 ± 79 | 0.09 |
| Baseline CRP (mg/L) ⁎ | 10 ± 8.2 | 15 ± 14 | <0.001 | 10 ± 8.6 | 15 ± 14 | <0.001 |
| Peak CRP (mg/L) † | 87 ± 78 | 108 ± 96 | 0.02 | 85 ± 77 | 118 ± 96 | 0.004 |
Baseline CRP levels in the no-reflow group were significantly higher than in the reflow group (22 ± 18 vs 13 ± 12 mg/L, p <0.001). Compared with the patients with no previous statin therapy, baseline CRP levels were significantly lower in the statin pretreatment group, irrespective of the presence of hypercholesterolemia (10 ± 8.2 vs 15 ± 14 mg/L in the overall population, 10 ± 8.6 vs 15 ± 14 mg/L in patients with hypercholesterolemia, p <0.001 for all analyses; Table 3 ).
Angiographic no-reflow (3.9% vs 14%, p <0.001) and STR <30% (4.4% vs 11%, p = 0.002) were significantly less frequent; complete STR (70% vs 59%, p <0.001; Figure 1 ) and MBG 3 (50% vs 40%, p = 0.006; Figure 2 ) were significantly more common in the statin pretreatment group. Accordingly, peak CK-MB was lower (186 ± 134 vs 241 ± 187 IU/L, p <0.001) and LVEF was higher (49 ± 7.5% vs 46 ± 8.3%, p <0.001) in the statin pretreatment group ( Table 4 ). In the subgroup analysis of therapy using various statins, there were no significant difference with respect to these perfusion parameters among the 5 statin subgroups ( Table 5 ).
