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Impact of Long-term Statin Therapy on Postprocedural Myocardial Infarction in Patients Undergoing Nonemergency Percutaneous Coronary Intervention
Impact of Long-term Statin Therapy on Postprocedural Myocardial Infarction in Patients Undergoing Nonemergency Percutaneous Coronary Intervention Jonathan Gordin, MD, Ali Haider, MD, Rajesh V. Swaminathan, MD, Luke K. Kim, MD, Robert M. Minutello, MD, Geoffrey Bergman, MD, S. Chiu Wong, MD, and Dmitriy N. Feldman, MD* Periprocedural statin therapy has been shown to decrease the rate of myocardial infarctions (MIs) after percutaneous coronary intervention (PCI). However, the impact of long-term statin therapy on postprocedure MI remains unknown. We examined the impact of long-term statin therapy on cardiac enzyme (cardiac troponin I [cTnI] and creatine kinase-MB [CK-MB]) increases after PCI in patients undergoing nonemergency PCI. Using the 2004/2005 Cornell Angioplasty Registry, we evaluated 1,482 patients undergoing elective or urgent PCI with normal preprocedure cardiac enzymes levels (cTnI and CKMB). The population was divided into 2 groups: (1) patients on long-term (>7 days) statin therapy before PCI (n ⴝ 1,073) and (2) patients not on long-term statin regimen (n ⴝ 409). Cardiac enzyme levels after PCI were assessed at 8, 12, and 18 hours after PCI. An increase in cTnI >1 time upper-limit of normal (ULN) was observed in 830 patients (56.1%) and an increase in cTnI >3 times ULN was observed in 518 patients (35.0%). There was no difference in incidence of cTnI increases >3 times ULN in patients on long-term statin therapy versus those not on long-term statin therapy in the overall group (35.1% vs 34.5%, p ⴝ 0.855). There was a trend toward a lower incidence of small cTnI increases >1 time ULN in patients on long-term statin therapy versus those not receiving long-term statins (54.6% vs 59.7%, p ⴝ 0.090). Incidence of CK-MB increases >1 time or >3 times ULN and peak cTnI and CK-MB levels were similar between the 2 groups. In a subgroup of patients with unstable angina, long-term statin therapy decreased small cTnI increases (>1 time ULN) after PCI (54.6% vs 64.3%, p ⴝ 0.023). The greatest benefit in decrease of MIs after PCI was seen in patients with unstable angina receiving long-term high-dose statin therapy. In conclusion, long-term statin therapy did not decrease the incidence of periprocedural MI in patients with stable coronary artery disease undergoing nonemergency PCI. In patients with unstable coronary syndromes, long-term statin therapy may be beneficial, particularly at a high dose. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110: 1397–1404) Increases of cardiac enzymes after nonemergency percutaneous coronary intervention (PCI) are not uncommon and have been associated with an increased risk of cardiovascular events during follow-up.1,2 Benefits of statin therapy have been well established in primary and secondary preventions of cardiovascular disease.3–5 These benefits may result from long-term low-density lipoprotein cholesterol lowering and short-term pleiotropic effects of statins.6 –12 Recent randomized controlled studies have demonstrated that a short course of preprocedural high-dose statin therapy may decrease the incidence of postprocedure myocardial infarction (MI) and subsequently decrease the incidence of major adverse cardiovascular events after PCI.13–15 However, there are limited data examining the protective effects Greenberg Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, New York. Manuscript received May 19, 2012; revised manuscript received and accepted June 25, 2012. *Corresponding author: Tel: 212-746-4644; fax: 212-746-8295. E-mail address: [email protected] (D.N. Feldman). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.06.052
of long-term statin therapy on the incidence of cardiac enzyme increases after PCI and PCI-related MI.16,17 The aim of this study was to examine the effect of long-term statin therapy on incidence of MI after PCI in a large cohort of patients undergoing nonemergency PCI in the current era of drug-eluting stenting. Methods Methods for data collection in this study have been previously described in detail.18 All patients undergoing PCI at New York Presbyterian Hospital, Weill Cornell Medical College (New York, New York) were enrolled in the Cornell Angioplasty Registry. A standard case-report form delineating comprehensive patient demographics, preintervention clinical status, procedural findings, and in-hospital complications was completed for each PCI performed. Patient follow-up was obtained by publicly available mortality data through the Social Security Death Index19 and through regularly scheduled telephone contacts. The present study included all consecutive patients from January 1, 2004 www.ajconline.org
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Table 1 Baseline clinical characteristics of patients Variable
Age (years), mean ⫾ SD Men White Diabetes mellitus Body mass index (kg/m2), mean ⫾ SD Current congestive heart failure Left ventricular ejection fraction (%), mean ⫾ SD Clinical presentation Stable angina pectoris Unstable angina pectoris Canadian Cardiovascular Society angina class III or IV Chronic obstructive pulmonary disease Peripheral vascular disease Previous stroke Previous heart failure Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft Hemoglobin level (g/dl), mean ⫾ SD Creatinine clearance (ml/min), mean ⫾ SD Creatinine clearance ⬍60 ml/ min Long-term aspirin therapy Long-term clopidogrel therapy
Table 2 Procedural characteristics
Statin Therapy
p Value
Yes (n ⫽ 1,073)
No (n ⫽ 409)
67.0 ⫾ 11.3 72.1% 78.8% 35.1% 28.6 ⫾ 5.1
67.1 ⫾ 11.7 67.7% 78.0% 21.5% 28.4 ⫾ 5.4
5.4% 51.6 ⫾ 9.5
6.8% 51.4 ⫾ 9.6
0.320 0.721
51.7% 48.3% 49.3%
51.3% 48.7% 50.4%
0.908 0.908 0.728
4.8%
5.1%
0.787
7.2% 9.2% 2.5% 36.3% 39.1%
7.3% 4.4% 2.4% 21.8% 18.1%
0.911 0.002 1.000 ⬍0.001 ⬍0.001
19.0%
10.8%
⬍0.001
13.0 ⫾ 1.6
13.3 ⫾ 1.7
0.005
76.2 ⫾ 31.6
78.3 ⫾ 32.2
0.251
34.1%
31.5%
0.356
79.0% 16.0%
60.4% 6.1%
⬍0.001 ⬍0.001
0.910 0.097 0.777 ⬍0.001 0.536
through December 31, 2005. Only patients with normal preprocedural cardiac troponin I (cTnI) levels (⬍0.15 ng/ ml) and normal preprocedural creatine kinase-MB (CKMB) levels (⬍4.5 ng/ml) were included in the study. Patients presenting with MI ⱕ7 days, hemodynamic instability/shock, receiving thrombolytic therapy ⱕ7 days, or with severe renal insufficiency (serum creatinine ⱖ4 mg/dl) were excluded. The study was approved by the institutional review board of Weill Cornell Medical College. Blood samples for cardiac markers (CK, CK-MB, and cTnI) were obtained routinely before PCI and at 8, 12, and 18 hours after PCI. cTnI analysis was performed using a Bayer ACS: ADVIA Centaur assay (Bayer, Pittsburgh, Pennsylvania).20 Patients were defined to have been on long-term statin therapy if they reported the use of a hydroxymethylglutaryl coenzyme A reductase inhibitor (including a statin as part of a combination pill) for ⱖ7 days before PCI and statins were continued after PCI. Patients were considered in the “nostatin” group if they did not report statin use before PCI and did not receive statin therapy immediately before PCI. Patients were excluded from the study if the timing of periprocedural statin therapy was missing. Patients on long-term statin therapy whose statin therapy was interrupted before PCI were excluded. Patients who were not on long-term
Variable
Nature of procedure Elective Urgent Number of narrowed coronary arteries 1 2 3 Multivessel or left main coronary artery disease Target percutaneous coronary intervention coronary artery Left anterior descending Right Left circumflex Left main Saphenous vein graft Multivessel or left main percutaneous coronary intervention Multilesion percutaneous coronary intervention Device used Stent Drug-eluting stent Sirolimus-eluting stent Paclitaxel-eluting stent Intravascular ultrasound Glycoprotein IIb/IIIa used Abciximab Other glycoprotein IIb/IIIa agents Clopidogrel loading dose ⱕ300 mg Clopidogrel loading dose 600 mg Stenosis severity before percutaneous coronary intervention (%), mean ⫾ SD Stenosis severity after percutaneous coronary intervention (%), mean ⫾ SD
Statin Therapy
p Value
Yes (n ⫽ 1,073)
No (n ⫽ 409)
63.4% 36.6%
65.0% 35.0%
0.586 0.586
39.0% 36.3% 24.7% 54.3%
44.7% 33.3% 22.0% 48.7%
0.051 0.302 0.323 0.055
45.7% 32.1% 30.5% 2.1% 4.8% 14.4%
57.5% 30.3% 21.3% 0.7% 4.2% 13.0%
⬍0.001 0.532 ⬍0.001 0.076 0.679 0.504
47.4%
44.7%
0.382
95.0% 89.1% 69.4% 21.2% 18.9% 48.0% 7.0% 41.0%
92.4% 86.1% 69.2% 18.3% 19.1% 51.3% 6.1% 45.2%
0.062 0.105 0.950 0.249 0.941 0.269 0.643 0.142
62.8%
37.2%
⬍0.001
53.1% 82.5 ⫾ 11.6
46.9% 84.0 ⫾ 11.0
0.002 0.032
2.9 ⫾ 10.1
2.9 ⫾ 10.4
0.994
statin therapy and received ⱖ1 dose of statins before PCI were excluded from analysis. High-dose statin therapy was defined as receiving simvastatin ⱖ40 mg/day, atorvastatin ⱖ20 mg/day, or any dose of rosuvastatin. All other statin doses were classified as low-dose statin therapy. Baseline characteristics and angiographic and procedural data in patients with versus without long-term statin therapy were compared. Primary end points analyzed were cTnI and CK-MB increases ⱖ1 time and ⱖ3 times upper limit of normal (ULN) after PCI. Secondary end point was longterm all-cause mortality. Long-term mortality data were obtained for 98.6% of patients using the Social Security Death Index with a mean follow-up period of 69.9 ⫾ 12.3 months. Multivessel disease was defined as the presence of ⬎70% lesion in ⱖ2 major coronary arteries/branches or a left main coronary artery lesion. Multivessel PCI was de-
Coronary Artery Disease/Long-term Statin Therapy and Postprocedure MI After PCI Table 3 In-hospital outcomes after percutaneous coronary intervention Variable
Angiographic success Death Emergency revascularization Stroke Renal failure Access site injury Stent thrombosis Bleeding Major Minor Length of stay (total) (days) 1–2 3–4 ⱖ5 Length of stay (after percutaneous coronary intervention) (days) 1–2 3–4 ⱖ5 Troponin I ⱖ1 time upper limit of normal Troponin I ⱖ3 times upper limit of normal Creatine kinase-MB ⱖ1 time upper limit of normal Creatine kinase-MB ⱖ3 times upper limit of normal Median creatine kinase-MB peak (ng/ml)* Median troponin I peak (ng/ml)†
Statin Therapy
p Value
Table 4 Multivariate predictors of troponin I increases at least three times upper limit of normal (multivariate logistic regression analysis) Variable
Yes (n ⫽ 1,073)
No (n ⫽ 409)
99.7% 0.0% 0.2% 0.0% 0.1% 0.7% 0.0%
99.5% 0.0% 0.0% 0.2% 0.0% 0.5% 0.0%
0.620 1.000 1.000 0.276 1.000 1.000 1.000
0.6% 9.6%
0.5% 9.5%
1.000 1.000
78.2% 11.6% 10.3%
83.9% 8.3% 7.8%
0.017 0.074 0.168
88.0% 7.2% 4.8% 54.6%
89.0% 6.8% 4.2% 59.7%
0.652 0.910 0.679 0.090
35.1%
34.5%
0.855
10.6%
10.8%
0.925
5.8%
5.6%
1.000
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Canadian Cardiovascular Society angina class III or IV Previous percutaneous coronary intervention Urgent procedure Multilesion percutaneous coronary intervention Previous myocardial infarction Long-term statin therapy
Chi-Square
HR
95% CI
p Value
12.47
1.50
1.20–1.88
⬍0.001
3.69
0.76
0.58–1.006
4.96 35.9
1.29 2.12
1.03–1.60 1.66–2.71
0.026 ⬍0.001
3.75
1.29
0.99–1.67
0.053
0.20
1.03
0.90–1.17
0.651
0.055
CI ⫽ confidence interval; HR ⫽ hazard ratio.
11.9
11.8
0.961
0.7
0.6
0.080
* Calculation only includes those with any creatine kinase-MB increase (n ⫽ 197). † Calculation only includes those with any troponin I increase (n ⫽ 832).
fined as a coronary intervention in ⱖ2 major coronary arteries/branches or a left main coronary artery. Congestive heart failure referred to New York Heart Association class III or IV heart failure during admission. Vascular injury referred to an access site complication requiring mechanical intervention. Major bleeding was defined as a decrease in hemoglobin ⱖ4 g/dl. Minor bleeding was defined as decreases in hemoglobin ⱖ2 and ⬍4 g/dl. Angiographic success was defined as final stenosis ⱕ20% of the target vessel reference diameter. Data management and analysis were performed with Excel 12.2.7 (Microsoft Corporation, Redmond, Washington) and SPSS Statistics 18.0 (IBM Corporation, Somert, New York). Data are presented as mean ⫾ SD for continuous variables or proportions for dichotomous variables. Differences in prevalence between groups were compared with chi-square test or Fisher’s exact test for dichotomous variables, and mean values for continuous variables were compared with Student’s t test. A p value ⬍0.05 was considered statistically significant. The relation of long-term statin therapy to the risk of cTnI increase after PCI was assessed with multivariate regression models. Univariate associations with cardiac enzyme increases were estimated
for all clinical and procedural variables (Tables 1 and 2). To test the independence of long-term statin therapy as a predictor of cardiac enzymes increases, long-term statin therapy was entered into the stepwise multivariate logistic regression model that also included univariate predictors of cardiac enzyme increases (significant at level of 0.15). Mortality rates were calculated and plotted according to Kaplan–Meier methods, and comparisons between groups were performed using log-rank statistic. Results During the study period, there were 3,611 elective or urgent PCIs performed in 2,504 consecutive patients. Of these, 1,482 patients met the inclusion criteria and were included in the final analysis. There were 1,073 patients (72.4%) taking statins for ⱖ7 days before PCI and periprocedurally and 409 patients (27.6%) who were not on longterm statin therapy and did not receive such therapy before PCI. In our study population, atorvastatin (59%) and simvastatin (26%) were the most frequently used statins, whereas pravastatin, rosuvastatin, lovastatin, and fluvastatin were used less commonly. There were 830 patients (56.1%) with increased cTnI levels ⱖ1 time ULN (median 0.20 ng/ml, mean 0.27 ⫾ 0.08) after PCI. There were 518 patients (35.0%) with increased cTnI levels ⱖ3 times ULN (median 1.50 ng/ml, mean 4.67 ⫾ 11.12) after PCI. Baseline characteristics of study patients are listed in Table 1. Patients receiving long-term statin therapy were more likely to have a history of diabetes mellitus, stroke, MI, PCI or coronary artery bypass graft surgery and were more likely to be on long-term aspirin or clopidogrel therapy. A similar proportion of patients presented with unstable angina in the 2 groups. Angiographic and procedural characteristics are presented in Table 2. There was a trend toward a higher frequency of single-vessel coronary artery disease (CAD) in the no-statin therapy group, whereas multivessel or left main coronary artery disease was more common in the long-term statin therapy group. The 2 groups had a high rate of stent (⬎92%) and drug-eluting stent (⬎86%) placement during PCI. There was a high rate of angiographic success (⬎99%) in all patients and a low rate of in-hospital events as listed in Table 3. Most patients in the
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Figure 1. Cardiac enzyme increases after percutaneous coronary intervention based on clinical presentation (upper limit of normal for troponin I 0.15 ng/ml).
Figure 2. Cardiac enzyme increases after percutaneous coronary intervention based on periprocedural use of glycoprotein (GP) IIb/IIIa inhibitors.
2 groups had a short (1 day to 2 days) length of stay in total and after PCI. Rates of cTnI increase ⱖ1 time ULN were comparable in the 2 groups, with a nonsignificant trend (p ⫽ 0.090) toward a higher incidence of cTnI increase ⱖ1 time ULN (59.7%) in the no-statin group versus long-term statin therapy group (54.6%) as presented in Table 3. Incidence of cTnI increase ⱖ3 times ULN was similar in the 2 groups, as were median cTnI peak levels. Increases of the less sensitive CK-MB enzyme ⱖ1 time and ⱖ3 times ULN and median CK-MB peak levels were nearly identical between the 2 groups. After adjustment for confounding variables with multivari-
ate logistic regression analysis, long-term statin therapy was not found to be an independent predictor of cTnI increase ⱖ3 times ULN after PCI (chi-square 0.20, hazard ratio 1.03, 95% confidence interval 0.90 to 1.17, p ⫽ 0.651; Table 4). Other independent predictors of cTnI increase ⱖ3 times ULN identified in a multivariate model were multilesion PCI, Canadian Cardiovascular Society angina class III or IV, and urgency of the procedure and are listed in Table 4. A subgroup analysis based on clinical presentation showed that in patients with unstable angina, there was an increase in the incidence of small cTnI increases ⱖ1 time ULN in the no-statin therapy group versus long-term statin
Coronary Artery Disease/Long-term Statin Therapy and Postprocedure MI After PCI
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Figure 3. Cardiac enzyme increases after percutaneous coronary intervention based on long-term use of clopidogrel at home.
therapy group (64.3% vs 54.6%, p ⫽ 0.023; Figure 1). However, rates of cTnI increases ⱖ3 times ULN were similar in the 2 groups. Further analysis also demonstrated a similar incidence of CK-MB increases and median peak cTnI and CK-MB increases between the no-statin therapy and long-term statin therapy groups within the unstable angina subgroup. A subgroup analysis based on periprocedural use of glycoprotein IIb/IIIa inhibitors (Figure 2) revealed similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) in those receiving versus not receiving glycoprotein IIb/IIIa agents. This is likely because patients who were not receiving unfractionated heparin plus glycoprotein IIb/IIIa inhibitors were treated with bivalirudin rather than with unfractionated heparin. Importantly, similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) were seen in the long-term statin therapy versus no long-term statin therapy groups independent of glycoprotein IIb/IIIa inhibitors. A subgroup analysis based on long-term clopidogrel use at home (Figure 3) demonstrated similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) in the long-term statin therapy versus no long-term statin therapy groups independently of long-term clopidogrel use at home. A subgroup analysis based on statin dose (Figure 4) demonstrated that in patients receiving high-dose long-term statin therapy, long-term high-dose statin therapy did not significantly decrease the incidence of cTnI increases ⱖ1 time or ⱖ3 times ULN (Figure 4). However, in patients with unstable angina, long-term high-dose statin therapy decreased the incidence of cTnI increases ⱖ1 time ULN (52.5% vs 64.3%, p ⫽ 0.009) and cTnI increases ⱖ3 times ULN (31.5% vs 40.2%, p ⫽ 0.004). In patients receiving low-dose long-term statin therapy, long-term low-dose statin therapy did not decrease the incidence of cTnI increases ⱖ1 time or ⱖ3 times ULN (Figure 4). By the end of the follow-up period, overall all-cause mortality rate was 10.1% in the population analyzed. Kaplan–Meier survival rates
were similar in long-term statin group versus no long-term statin group (88.5% vs 87.8%, p ⫽ 0.789, log-rank test; Figure 5). Discussion This study represents a comprehensive evaluation of short-term outcomes in patients with and without long-term statin therapy presenting with normal cTnI and CK-MB levels before nonemergency PCI. There were several major findings in the present study: (1) long-term statin use did not affect the incidence of postprocedure MI, defined as cTnI or CK-MB increase ⱖ1 time or ⱖ3 times ULN; (2) long-term statin use did not decrease in-hospital adverse events or long-term all-cause mortality; (3) lack of benefit of longterm statin use on MI decrease after PCI was not affected by periprocedural glycoprotein IIb/IIIa inhibitor use or long-term clopidogrel therapy; and (4) in a subgroup of patients with unstable angina, long-term statin therapy decreased small cTnI increases (ⱖ1 time ULN) after PCI. The greatest benefit in decrease of cTnI increases after PCI was seen in patients with unstable angina receiving long-term high-dose statin therapy. Previous randomized studies have evaluated the effect of statin therapy on postprocedure MI, but limited data are available examining the benefit for patients presenting on long-term statin therapy. The Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA) trial14 examined the effect of preprocedural atorvastatin 40 mg 7-days before PCI in stable statin-naive patients. This study demonstrated a significant decrease in the incidence of increased postprocedure biomarkers (CK-MB, TnI, myoglobin) in statin-treated patients with a decrease in MIs by CK-MB determination (⬎2 times ULN) after PCI (5% of patients in statin group vs 18% of those in placebo group, p ⫽ 0.025). The Novel Approaches for Preventing or Limiting Events (NAPLES) II trial examined the effect of a single high (80-mg) loading dose of atorvastatin within 24
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Figure 4. Cardiac enzyme increases after percutaneous coronary intervention based on presenting symptoms and (A) high-dose and (B) low-dose statin.
hours of PCI in statin-naive patients undergoing elective PCI.15 The investigators found a significantly lower rate of CK-MB and TnI increases ⬎3 times ULN in the statin compared with control group (CK-MB ⬎3 times ULN 9.5% vs 15.8%, p ⫽ 0.014; TnI ⬎3 times ULN 26.6% vs 39.1%, p ⬍0.001). Two previous smaller studies have examined the effect of long-term statin use on postprocedure MIs. Mulukutla et al16 demonstrated a difference in the incidence of CK-MB increases ⬎3 times ULN in 425 patients undergoing elective PCI on long-term statin therapy versus those who were not receiving long-term statin therapy (2.2% vs 7.3%, p ⫽ 0.01). Auguadro et al17 examined 552 patients undergoing nonemergency PCI divided into 2 groups based on statin therapy in the 3 months before PCI. They showed that
patients on long-term statin therapy had a lower incidence of cTnI increases ⱖ0.3 ng/ml (29% vs 48%, p ⬍0.001) and lower incidence of CK-MB increase ⬎1 time ULN (7% vs 12%, p ⫽ 0.04). Incidence of CK-MB and cTnI increases in their control group appears to be similar to those in our study (11% and 60%, respectively). However, these 2 previous studies had a relatively small sample size and the results may have been affected by the higher-risk patient population examined, different statin doses, longer duration of statin therapy, and periprocedural factors that were not controlled for such as baseline renal insufficiency/failure and preprocedural clopidogrel pretreatment. In contrast, our study had examined a larger sample and incorporated a thorough assessment of potential confounding variables using multivariate modeling.
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Figure 5. All-cause long-term survival based on long-term statin-use status.
The ARMYDA-RECAPTURE trial randomized 383 patients presenting with stable CAD and acute coronary syndromes already on long-term statin therapy to atorvastatin reload 80 mg 12 hours before PCI (with a further 40-mg preprocedural dose) or placebo.21 They found a decreased incidence of major adverse cardiovascular events in the statin-reloading arm at 30 days driven by a decrease in periprocedural MIs. There was a lower incidence of CK-MB increases ⬎1 time ULN (13% vs 24%, p ⫽ 0.017) and cTnI increases ⬎1 time ULN (37% vs 49%, p ⫽ 0.021). Importantly, their subgroup analysis demonstrated that the benefit of statins was mainly present in patients presenting with acute coronary syndromes and not in those with stable CAD. Our study did not evaluate the immediate effects of a statin loading dose; however, the subgroup analysis suggested that patients presenting with acute coronary syndromes benefited most from long-term high-dose statin therapy. In aggregate, these data suggest that patients with unstable coronary syndromes may derive the greatest benefit from long-term high-dose statin therapy and reloading with a high-dose statin for postprocedure MI decrease. What is the mechanism by which statins decrease postprocedure myocardial necrosis? Given the effectiveness of periprocedural statins within 24 to 48 hours, the benefit of statin therapy on decrease of MIs after PCI may be due in part to their pleiotropic and anti-inflammatory effects.22,23 In patients undergoing PCI, statin therapy has been associated with a significant decrease in C-reactive protein levels after PCI and beneficial effects on endothelial function, microcirculation, cell adhesion, and platelet function.24 –27 Such beneficial effects of statins may be associated with
long-term statin therapy and periprocedural high-dose treatment. It is logical that these anti-inflammatory and endothelial benefits of statins will be particularly pronounced in patients with unstable plaque such as in those presenting with acute coronary syndromes. Our study suggests that long-term statin therapy may not offer a protective effect for a decrease in MI or biomarker release after PCI in patients with stable CAD. In patients with unstable coronary syndromes, long-term statin therapy may be beneficial, particularly at a high dose. Randomized trial data suggest that pretreatment with statins before PCI in statin-naive patients is beneficial. In contrast, loading of a high-dose of statin before PCI in patients on long-term statin therapy may be of benefit only in patients presenting with acute coronary syndromes. Given the benefits and minimal risks associated with periprocedural loading with statins, we suggest that preprocedural loading with a highdose statin should be strongly considered, particularly in patients presenting with acute coronary syndromes. We acknowledge several limitations in this study. First, our analysis was derived from a single high-volume tertiary care center population. Second, although data in the present study were collected prospectively, this is a retrospective analysis and is subject to the limitations of such analyses. Third, type of statin, dose, or duration of treatment could have affected the results of the study. Also, duration of long-term statin therapy (ⱖ7 days before PCI) may have been sufficient for pleiotropic, but not for lipid-lowering, effects of statins. Fourth, although specific data on periprocedural complications including side branch occlusion and no-reflow phenomena were not available, the large number
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of patients in the 2 groups would likely decrease any significant impact of these differences. 1. Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997;277:461– 466. 2. Prasad A, Singh M, Lerman A, Lennon RJ, Holmes DR, Rihal CS. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006;48:1765–1770. 3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301– 1307. 4. Tikkanen MJ, Szarek M, Fayyad R, Holme I, Cater NB, Faergerman O, Kastelein JJ, Olsson AG, Larsen ML, Lindahl C, Pedersen TR; IDEAL Investigators. Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. J Am Coll Cardiol 2009;54:2353–2357. 5. Arca M, Gaspardone A. Atorvastatin efficacy in the primary and secondary prevention of cardiovascular events. Drugs 2007;67(suppl 1):29 – 42. 6. Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis 2009;203:325–330. 7. Tsunekawa T, Hayashi T, Kano H, Sumi D, Matsui-Hirai H, Thakur NK, Egashira K, Iguchi A. Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001;104:376 – 379. 8. Hinoi T, Matsuo S, Tadehara F, Tsujiyama S, Yamakido M. Acute effect of atorvastatin on coronary circulation measured by transthoracic Doppler echocardiography in patients without coronary artery disease by angiography. Am J Cardiol 2005;96:89 –91. 9. Macin SM, Perna ER, Farías EF, Franciosi V, Cialzeta JR, Brizuela M, Medina F, Tajer C, Doval H, Badaracco R. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J 2005;149:451– 457. 10. Albert MA, Danielson E, Rifai N, Ridker PM; PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64 –70. 11. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001;103:2248 –2253. 12. Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005;111:412– 419. 13. Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, Montinaro A, Di Sciascio G. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007;49:1272–1278.
14. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G; ARMYDA Investigators. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) study. Circulation 2004;110:674 – 678. 15. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, Mussardo M, Montorfano M, Ricciardelli B, Colombo A. Novel Approaches for Preventing or Limiting Events (NAPLES) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol 2009;54:2157–2163. 16. Mulukutla SR, Marroquin OC, Smith C, Varghese R, Anderson WD, Lee JS, Cohen HA, Counihan PJ, Lee AB, Gulati V, McNamara D. Effect of statin therapy prior to elective percutaneous coronary intervention on frequency of periprocedural myocardial injury. Am J Cardiol 2004;94:1363–1366. 17. Auguadro C, Manfredi M, Scalise F, Mortara A, Specchia G. Protective role of chronic statin therapy in reducing myocardial damage during percutaneous coronary intervention. J Cardiovasc Med (Hagerstown) 2006;7:416 – 421. 18. Feldman DN, Minutello RM, Bergman G, Moussa I, Wong SC. Relation of troponin I levels following nonemergent percutaneous coronary intervention to short- and long-term outcomes. Am J Cardiol 2009;104:1210 –1215. 19. Sesso HD, Paffenbarger RS, Lee IM. Comparison of national death index and World Wide Web death searches. Am J Epidemiol 2000; 152:107–111. 20. Armstrong GP, Barker AN, Patel H, Hart HH. Reference interval for troponin I on the ACS:Centaur assay: a recommendation based on the recent redefinition of myocardial infarction. Clin Chem 2002;48:198 – 199. 21. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial. J Am Coll Cardiol 2009;54:558 –565. 22. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001; 103:1933–1935. 23. Strandberg TE, Vanhanen H, Tikkanen MJ. Effect of statins on C-reactive protein in patients with coronary artery disease. Lancet 1999; 353:118 –119. 24. Gaspardone A, Versaci F, Proietti I, Tomai F, Altamura L, Skossyreva O, Chiariello L. Effect of atorvastatin (80 mg) initiated at the time of coronary artery stent implantation on C-reactive protein and six-month clinical events. Am J Cardiol 2002;90:786 –789. 25. Ott I, Neumann FJ, Kenngott S, Gawaz M, Schömig A. Procoagulant inflammatory responses of monocytes after direct balloon angioplasty in acute myocardial infarction. Am J Cardiol 1998;82:938 –942. 26. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998;98: 224 –233. 27. Jones SP, Lefer DJ. Cardioprotective actions of acute HMG-CoA reductase inhibition in the setting of myocardial infarction. Acta Physiol Scand 2001;173:139 –143.
of long-term statin therapy on the incidence of cardiac enzyme increases after PCI and PCI-related MI.16,17 The aim of this study was to examine the effect of long-term statin therapy on incidence of MI after PCI in a large cohort of patients undergoing nonemergency PCI in the current era of drug-eluting stenting. Methods Methods for data collection in this study have been previously described in detail.18 All patients undergoing PCI at New York Presbyterian Hospital, Weill Cornell Medical College (New York, New York) were enrolled in the Cornell Angioplasty Registry. A standard case-report form delineating comprehensive patient demographics, preintervention clinical status, procedural findings, and in-hospital complications was completed for each PCI performed. Patient follow-up was obtained by publicly available mortality data through the Social Security Death Index19 and through regularly scheduled telephone contacts. The present study included all consecutive patients from January 1, 2004 www.ajconline.org
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Table 1 Baseline clinical characteristics of patients Variable
Age (years), mean ⫾ SD Men White Diabetes mellitus Body mass index (kg/m2), mean ⫾ SD Current congestive heart failure Left ventricular ejection fraction (%), mean ⫾ SD Clinical presentation Stable angina pectoris Unstable angina pectoris Canadian Cardiovascular Society angina class III or IV Chronic obstructive pulmonary disease Peripheral vascular disease Previous stroke Previous heart failure Previous myocardial infarction Previous percutaneous coronary intervention Previous coronary artery bypass graft Hemoglobin level (g/dl), mean ⫾ SD Creatinine clearance (ml/min), mean ⫾ SD Creatinine clearance ⬍60 ml/ min Long-term aspirin therapy Long-term clopidogrel therapy
Table 2 Procedural characteristics
Statin Therapy
p Value
Yes (n ⫽ 1,073)
No (n ⫽ 409)
67.0 ⫾ 11.3 72.1% 78.8% 35.1% 28.6 ⫾ 5.1
67.1 ⫾ 11.7 67.7% 78.0% 21.5% 28.4 ⫾ 5.4
5.4% 51.6 ⫾ 9.5
6.8% 51.4 ⫾ 9.6
0.320 0.721
51.7% 48.3% 49.3%
51.3% 48.7% 50.4%
0.908 0.908 0.728
4.8%
5.1%
0.787
7.2% 9.2% 2.5% 36.3% 39.1%
7.3% 4.4% 2.4% 21.8% 18.1%
0.911 0.002 1.000 ⬍0.001 ⬍0.001
19.0%
10.8%
⬍0.001
13.0 ⫾ 1.6
13.3 ⫾ 1.7
0.005
76.2 ⫾ 31.6
78.3 ⫾ 32.2
0.251
34.1%
31.5%
0.356
79.0% 16.0%
60.4% 6.1%
⬍0.001 ⬍0.001
0.910 0.097 0.777 ⬍0.001 0.536
through December 31, 2005. Only patients with normal preprocedural cardiac troponin I (cTnI) levels (⬍0.15 ng/ ml) and normal preprocedural creatine kinase-MB (CKMB) levels (⬍4.5 ng/ml) were included in the study. Patients presenting with MI ⱕ7 days, hemodynamic instability/shock, receiving thrombolytic therapy ⱕ7 days, or with severe renal insufficiency (serum creatinine ⱖ4 mg/dl) were excluded. The study was approved by the institutional review board of Weill Cornell Medical College. Blood samples for cardiac markers (CK, CK-MB, and cTnI) were obtained routinely before PCI and at 8, 12, and 18 hours after PCI. cTnI analysis was performed using a Bayer ACS: ADVIA Centaur assay (Bayer, Pittsburgh, Pennsylvania).20 Patients were defined to have been on long-term statin therapy if they reported the use of a hydroxymethylglutaryl coenzyme A reductase inhibitor (including a statin as part of a combination pill) for ⱖ7 days before PCI and statins were continued after PCI. Patients were considered in the “nostatin” group if they did not report statin use before PCI and did not receive statin therapy immediately before PCI. Patients were excluded from the study if the timing of periprocedural statin therapy was missing. Patients on long-term statin therapy whose statin therapy was interrupted before PCI were excluded. Patients who were not on long-term
Variable
Nature of procedure Elective Urgent Number of narrowed coronary arteries 1 2 3 Multivessel or left main coronary artery disease Target percutaneous coronary intervention coronary artery Left anterior descending Right Left circumflex Left main Saphenous vein graft Multivessel or left main percutaneous coronary intervention Multilesion percutaneous coronary intervention Device used Stent Drug-eluting stent Sirolimus-eluting stent Paclitaxel-eluting stent Intravascular ultrasound Glycoprotein IIb/IIIa used Abciximab Other glycoprotein IIb/IIIa agents Clopidogrel loading dose ⱕ300 mg Clopidogrel loading dose 600 mg Stenosis severity before percutaneous coronary intervention (%), mean ⫾ SD Stenosis severity after percutaneous coronary intervention (%), mean ⫾ SD
Statin Therapy
p Value
Yes (n ⫽ 1,073)
No (n ⫽ 409)
63.4% 36.6%
65.0% 35.0%
0.586 0.586
39.0% 36.3% 24.7% 54.3%
44.7% 33.3% 22.0% 48.7%
0.051 0.302 0.323 0.055
45.7% 32.1% 30.5% 2.1% 4.8% 14.4%
57.5% 30.3% 21.3% 0.7% 4.2% 13.0%
⬍0.001 0.532 ⬍0.001 0.076 0.679 0.504
47.4%
44.7%
0.382
95.0% 89.1% 69.4% 21.2% 18.9% 48.0% 7.0% 41.0%
92.4% 86.1% 69.2% 18.3% 19.1% 51.3% 6.1% 45.2%
0.062 0.105 0.950 0.249 0.941 0.269 0.643 0.142
62.8%
37.2%
⬍0.001
53.1% 82.5 ⫾ 11.6
46.9% 84.0 ⫾ 11.0
0.002 0.032
2.9 ⫾ 10.1
2.9 ⫾ 10.4
0.994
statin therapy and received ⱖ1 dose of statins before PCI were excluded from analysis. High-dose statin therapy was defined as receiving simvastatin ⱖ40 mg/day, atorvastatin ⱖ20 mg/day, or any dose of rosuvastatin. All other statin doses were classified as low-dose statin therapy. Baseline characteristics and angiographic and procedural data in patients with versus without long-term statin therapy were compared. Primary end points analyzed were cTnI and CK-MB increases ⱖ1 time and ⱖ3 times upper limit of normal (ULN) after PCI. Secondary end point was longterm all-cause mortality. Long-term mortality data were obtained for 98.6% of patients using the Social Security Death Index with a mean follow-up period of 69.9 ⫾ 12.3 months. Multivessel disease was defined as the presence of ⬎70% lesion in ⱖ2 major coronary arteries/branches or a left main coronary artery lesion. Multivessel PCI was de-
Coronary Artery Disease/Long-term Statin Therapy and Postprocedure MI After PCI Table 3 In-hospital outcomes after percutaneous coronary intervention Variable
Angiographic success Death Emergency revascularization Stroke Renal failure Access site injury Stent thrombosis Bleeding Major Minor Length of stay (total) (days) 1–2 3–4 ⱖ5 Length of stay (after percutaneous coronary intervention) (days) 1–2 3–4 ⱖ5 Troponin I ⱖ1 time upper limit of normal Troponin I ⱖ3 times upper limit of normal Creatine kinase-MB ⱖ1 time upper limit of normal Creatine kinase-MB ⱖ3 times upper limit of normal Median creatine kinase-MB peak (ng/ml)* Median troponin I peak (ng/ml)†
Statin Therapy
p Value
Table 4 Multivariate predictors of troponin I increases at least three times upper limit of normal (multivariate logistic regression analysis) Variable
Yes (n ⫽ 1,073)
No (n ⫽ 409)
99.7% 0.0% 0.2% 0.0% 0.1% 0.7% 0.0%
99.5% 0.0% 0.0% 0.2% 0.0% 0.5% 0.0%
0.620 1.000 1.000 0.276 1.000 1.000 1.000
0.6% 9.6%
0.5% 9.5%
1.000 1.000
78.2% 11.6% 10.3%
83.9% 8.3% 7.8%
0.017 0.074 0.168
88.0% 7.2% 4.8% 54.6%
89.0% 6.8% 4.2% 59.7%
0.652 0.910 0.679 0.090
35.1%
34.5%
0.855
10.6%
10.8%
0.925
5.8%
5.6%
1.000
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Canadian Cardiovascular Society angina class III or IV Previous percutaneous coronary intervention Urgent procedure Multilesion percutaneous coronary intervention Previous myocardial infarction Long-term statin therapy
Chi-Square
HR
95% CI
p Value
12.47
1.50
1.20–1.88
⬍0.001
3.69
0.76
0.58–1.006
4.96 35.9
1.29 2.12
1.03–1.60 1.66–2.71
0.026 ⬍0.001
3.75
1.29
0.99–1.67
0.053
0.20
1.03
0.90–1.17
0.651
0.055
CI ⫽ confidence interval; HR ⫽ hazard ratio.
11.9
11.8
0.961
0.7
0.6
0.080
* Calculation only includes those with any creatine kinase-MB increase (n ⫽ 197). † Calculation only includes those with any troponin I increase (n ⫽ 832).
fined as a coronary intervention in ⱖ2 major coronary arteries/branches or a left main coronary artery. Congestive heart failure referred to New York Heart Association class III or IV heart failure during admission. Vascular injury referred to an access site complication requiring mechanical intervention. Major bleeding was defined as a decrease in hemoglobin ⱖ4 g/dl. Minor bleeding was defined as decreases in hemoglobin ⱖ2 and ⬍4 g/dl. Angiographic success was defined as final stenosis ⱕ20% of the target vessel reference diameter. Data management and analysis were performed with Excel 12.2.7 (Microsoft Corporation, Redmond, Washington) and SPSS Statistics 18.0 (IBM Corporation, Somert, New York). Data are presented as mean ⫾ SD for continuous variables or proportions for dichotomous variables. Differences in prevalence between groups were compared with chi-square test or Fisher’s exact test for dichotomous variables, and mean values for continuous variables were compared with Student’s t test. A p value ⬍0.05 was considered statistically significant. The relation of long-term statin therapy to the risk of cTnI increase after PCI was assessed with multivariate regression models. Univariate associations with cardiac enzyme increases were estimated
for all clinical and procedural variables (Tables 1 and 2). To test the independence of long-term statin therapy as a predictor of cardiac enzymes increases, long-term statin therapy was entered into the stepwise multivariate logistic regression model that also included univariate predictors of cardiac enzyme increases (significant at level of 0.15). Mortality rates were calculated and plotted according to Kaplan–Meier methods, and comparisons between groups were performed using log-rank statistic. Results During the study period, there were 3,611 elective or urgent PCIs performed in 2,504 consecutive patients. Of these, 1,482 patients met the inclusion criteria and were included in the final analysis. There were 1,073 patients (72.4%) taking statins for ⱖ7 days before PCI and periprocedurally and 409 patients (27.6%) who were not on longterm statin therapy and did not receive such therapy before PCI. In our study population, atorvastatin (59%) and simvastatin (26%) were the most frequently used statins, whereas pravastatin, rosuvastatin, lovastatin, and fluvastatin were used less commonly. There were 830 patients (56.1%) with increased cTnI levels ⱖ1 time ULN (median 0.20 ng/ml, mean 0.27 ⫾ 0.08) after PCI. There were 518 patients (35.0%) with increased cTnI levels ⱖ3 times ULN (median 1.50 ng/ml, mean 4.67 ⫾ 11.12) after PCI. Baseline characteristics of study patients are listed in Table 1. Patients receiving long-term statin therapy were more likely to have a history of diabetes mellitus, stroke, MI, PCI or coronary artery bypass graft surgery and were more likely to be on long-term aspirin or clopidogrel therapy. A similar proportion of patients presented with unstable angina in the 2 groups. Angiographic and procedural characteristics are presented in Table 2. There was a trend toward a higher frequency of single-vessel coronary artery disease (CAD) in the no-statin therapy group, whereas multivessel or left main coronary artery disease was more common in the long-term statin therapy group. The 2 groups had a high rate of stent (⬎92%) and drug-eluting stent (⬎86%) placement during PCI. There was a high rate of angiographic success (⬎99%) in all patients and a low rate of in-hospital events as listed in Table 3. Most patients in the
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Figure 1. Cardiac enzyme increases after percutaneous coronary intervention based on clinical presentation (upper limit of normal for troponin I 0.15 ng/ml).
Figure 2. Cardiac enzyme increases after percutaneous coronary intervention based on periprocedural use of glycoprotein (GP) IIb/IIIa inhibitors.
2 groups had a short (1 day to 2 days) length of stay in total and after PCI. Rates of cTnI increase ⱖ1 time ULN were comparable in the 2 groups, with a nonsignificant trend (p ⫽ 0.090) toward a higher incidence of cTnI increase ⱖ1 time ULN (59.7%) in the no-statin group versus long-term statin therapy group (54.6%) as presented in Table 3. Incidence of cTnI increase ⱖ3 times ULN was similar in the 2 groups, as were median cTnI peak levels. Increases of the less sensitive CK-MB enzyme ⱖ1 time and ⱖ3 times ULN and median CK-MB peak levels were nearly identical between the 2 groups. After adjustment for confounding variables with multivari-
ate logistic regression analysis, long-term statin therapy was not found to be an independent predictor of cTnI increase ⱖ3 times ULN after PCI (chi-square 0.20, hazard ratio 1.03, 95% confidence interval 0.90 to 1.17, p ⫽ 0.651; Table 4). Other independent predictors of cTnI increase ⱖ3 times ULN identified in a multivariate model were multilesion PCI, Canadian Cardiovascular Society angina class III or IV, and urgency of the procedure and are listed in Table 4. A subgroup analysis based on clinical presentation showed that in patients with unstable angina, there was an increase in the incidence of small cTnI increases ⱖ1 time ULN in the no-statin therapy group versus long-term statin
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Figure 3. Cardiac enzyme increases after percutaneous coronary intervention based on long-term use of clopidogrel at home.
therapy group (64.3% vs 54.6%, p ⫽ 0.023; Figure 1). However, rates of cTnI increases ⱖ3 times ULN were similar in the 2 groups. Further analysis also demonstrated a similar incidence of CK-MB increases and median peak cTnI and CK-MB increases between the no-statin therapy and long-term statin therapy groups within the unstable angina subgroup. A subgroup analysis based on periprocedural use of glycoprotein IIb/IIIa inhibitors (Figure 2) revealed similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) in those receiving versus not receiving glycoprotein IIb/IIIa agents. This is likely because patients who were not receiving unfractionated heparin plus glycoprotein IIb/IIIa inhibitors were treated with bivalirudin rather than with unfractionated heparin. Importantly, similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) were seen in the long-term statin therapy versus no long-term statin therapy groups independent of glycoprotein IIb/IIIa inhibitors. A subgroup analysis based on long-term clopidogrel use at home (Figure 3) demonstrated similar rates of cTnI increases (ⱖ1 time or ⱖ3 times ULN) in the long-term statin therapy versus no long-term statin therapy groups independently of long-term clopidogrel use at home. A subgroup analysis based on statin dose (Figure 4) demonstrated that in patients receiving high-dose long-term statin therapy, long-term high-dose statin therapy did not significantly decrease the incidence of cTnI increases ⱖ1 time or ⱖ3 times ULN (Figure 4). However, in patients with unstable angina, long-term high-dose statin therapy decreased the incidence of cTnI increases ⱖ1 time ULN (52.5% vs 64.3%, p ⫽ 0.009) and cTnI increases ⱖ3 times ULN (31.5% vs 40.2%, p ⫽ 0.004). In patients receiving low-dose long-term statin therapy, long-term low-dose statin therapy did not decrease the incidence of cTnI increases ⱖ1 time or ⱖ3 times ULN (Figure 4). By the end of the follow-up period, overall all-cause mortality rate was 10.1% in the population analyzed. Kaplan–Meier survival rates
were similar in long-term statin group versus no long-term statin group (88.5% vs 87.8%, p ⫽ 0.789, log-rank test; Figure 5). Discussion This study represents a comprehensive evaluation of short-term outcomes in patients with and without long-term statin therapy presenting with normal cTnI and CK-MB levels before nonemergency PCI. There were several major findings in the present study: (1) long-term statin use did not affect the incidence of postprocedure MI, defined as cTnI or CK-MB increase ⱖ1 time or ⱖ3 times ULN; (2) long-term statin use did not decrease in-hospital adverse events or long-term all-cause mortality; (3) lack of benefit of longterm statin use on MI decrease after PCI was not affected by periprocedural glycoprotein IIb/IIIa inhibitor use or long-term clopidogrel therapy; and (4) in a subgroup of patients with unstable angina, long-term statin therapy decreased small cTnI increases (ⱖ1 time ULN) after PCI. The greatest benefit in decrease of cTnI increases after PCI was seen in patients with unstable angina receiving long-term high-dose statin therapy. Previous randomized studies have evaluated the effect of statin therapy on postprocedure MI, but limited data are available examining the benefit for patients presenting on long-term statin therapy. The Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA) trial14 examined the effect of preprocedural atorvastatin 40 mg 7-days before PCI in stable statin-naive patients. This study demonstrated a significant decrease in the incidence of increased postprocedure biomarkers (CK-MB, TnI, myoglobin) in statin-treated patients with a decrease in MIs by CK-MB determination (⬎2 times ULN) after PCI (5% of patients in statin group vs 18% of those in placebo group, p ⫽ 0.025). The Novel Approaches for Preventing or Limiting Events (NAPLES) II trial examined the effect of a single high (80-mg) loading dose of atorvastatin within 24
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Figure 4. Cardiac enzyme increases after percutaneous coronary intervention based on presenting symptoms and (A) high-dose and (B) low-dose statin.
hours of PCI in statin-naive patients undergoing elective PCI.15 The investigators found a significantly lower rate of CK-MB and TnI increases ⬎3 times ULN in the statin compared with control group (CK-MB ⬎3 times ULN 9.5% vs 15.8%, p ⫽ 0.014; TnI ⬎3 times ULN 26.6% vs 39.1%, p ⬍0.001). Two previous smaller studies have examined the effect of long-term statin use on postprocedure MIs. Mulukutla et al16 demonstrated a difference in the incidence of CK-MB increases ⬎3 times ULN in 425 patients undergoing elective PCI on long-term statin therapy versus those who were not receiving long-term statin therapy (2.2% vs 7.3%, p ⫽ 0.01). Auguadro et al17 examined 552 patients undergoing nonemergency PCI divided into 2 groups based on statin therapy in the 3 months before PCI. They showed that
patients on long-term statin therapy had a lower incidence of cTnI increases ⱖ0.3 ng/ml (29% vs 48%, p ⬍0.001) and lower incidence of CK-MB increase ⬎1 time ULN (7% vs 12%, p ⫽ 0.04). Incidence of CK-MB and cTnI increases in their control group appears to be similar to those in our study (11% and 60%, respectively). However, these 2 previous studies had a relatively small sample size and the results may have been affected by the higher-risk patient population examined, different statin doses, longer duration of statin therapy, and periprocedural factors that were not controlled for such as baseline renal insufficiency/failure and preprocedural clopidogrel pretreatment. In contrast, our study had examined a larger sample and incorporated a thorough assessment of potential confounding variables using multivariate modeling.
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Figure 5. All-cause long-term survival based on long-term statin-use status.
The ARMYDA-RECAPTURE trial randomized 383 patients presenting with stable CAD and acute coronary syndromes already on long-term statin therapy to atorvastatin reload 80 mg 12 hours before PCI (with a further 40-mg preprocedural dose) or placebo.21 They found a decreased incidence of major adverse cardiovascular events in the statin-reloading arm at 30 days driven by a decrease in periprocedural MIs. There was a lower incidence of CK-MB increases ⬎1 time ULN (13% vs 24%, p ⫽ 0.017) and cTnI increases ⬎1 time ULN (37% vs 49%, p ⫽ 0.021). Importantly, their subgroup analysis demonstrated that the benefit of statins was mainly present in patients presenting with acute coronary syndromes and not in those with stable CAD. Our study did not evaluate the immediate effects of a statin loading dose; however, the subgroup analysis suggested that patients presenting with acute coronary syndromes benefited most from long-term high-dose statin therapy. In aggregate, these data suggest that patients with unstable coronary syndromes may derive the greatest benefit from long-term high-dose statin therapy and reloading with a high-dose statin for postprocedure MI decrease. What is the mechanism by which statins decrease postprocedure myocardial necrosis? Given the effectiveness of periprocedural statins within 24 to 48 hours, the benefit of statin therapy on decrease of MIs after PCI may be due in part to their pleiotropic and anti-inflammatory effects.22,23 In patients undergoing PCI, statin therapy has been associated with a significant decrease in C-reactive protein levels after PCI and beneficial effects on endothelial function, microcirculation, cell adhesion, and platelet function.24 –27 Such beneficial effects of statins may be associated with
long-term statin therapy and periprocedural high-dose treatment. It is logical that these anti-inflammatory and endothelial benefits of statins will be particularly pronounced in patients with unstable plaque such as in those presenting with acute coronary syndromes. Our study suggests that long-term statin therapy may not offer a protective effect for a decrease in MI or biomarker release after PCI in patients with stable CAD. In patients with unstable coronary syndromes, long-term statin therapy may be beneficial, particularly at a high dose. Randomized trial data suggest that pretreatment with statins before PCI in statin-naive patients is beneficial. In contrast, loading of a high-dose of statin before PCI in patients on long-term statin therapy may be of benefit only in patients presenting with acute coronary syndromes. Given the benefits and minimal risks associated with periprocedural loading with statins, we suggest that preprocedural loading with a highdose statin should be strongly considered, particularly in patients presenting with acute coronary syndromes. We acknowledge several limitations in this study. First, our analysis was derived from a single high-volume tertiary care center population. Second, although data in the present study were collected prospectively, this is a retrospective analysis and is subject to the limitations of such analyses. Third, type of statin, dose, or duration of treatment could have affected the results of the study. Also, duration of long-term statin therapy (ⱖ7 days before PCI) may have been sufficient for pleiotropic, but not for lipid-lowering, effects of statins. Fourth, although specific data on periprocedural complications including side branch occlusion and no-reflow phenomena were not available, the large number
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