Effect of Rosuvastatin Therapy on Troponin I Release Following Percutaneous Coronary Intervention in Nonemergency Patients (from the TIP 3 Study)




Several randomized studies have suggested that pretreatment with statins may reduce a periprocedural biomarker release in patients who underwent percutaneous coronary intervention (PCI); however, results remain controversial. The purpose of this study was to investigate the effect of a 1-day rosuvastatin therapy on troponin I release in patients who underwent nonemergency PCI. A total of 445 patients with angina pectoris were randomly assigned to therapy with rosuvastatin (20 mg 12 hours before coronary angiography + 20 mg immediately before PCI; rosuvastatin group, 220 patients) or PCI without statin therapy (control group, 225 patients). In patients taking statins (73%), rosuvastatin was added to their long-term statin therapy. The primary end point was the incidence of TnI microleak defined as TnI elevation >1.5× upper limit of normal, and the secondary end point was the incidence of post-PCI TnI elevation >3× upper limit of normal. The incidence of primary and secondary end point in the rosuvastatin versus control group was 13.6% versus 12% (p = 0.61) and 8.2% versus 7.1% (p = 0.67), respectively. Patients with C-reactive protein ≥2.0 mg/L had a decreased release of post-PCI TnI in the rosuvastatin group (0.032 [0.010 to 0.143] μg/L vs 0.056 [0.018 to 0.241] μg/L; p = 0.04). In conclusion, 1-day rosuvastatin therapy (20 mg twice a day) did not influence post-PCI TnI release in patients with angina. However, these results suggest that, in patients with an advanced inflammatory status, rosuvastatin loading therapy might have a cardioprotective effect.


The high postinterventional troponin I (TnI) release is considered to represent the myocardial injury or periprocedural myocardial infarction (PMI), which is a relatively common complication of percutaneous coronary intervention (PCI), mostly with a silent clinical course. Although the impact of PMI on long-term clinical prognosis is still on debate, several studies have demonstrated a relation between the incidence and extent of PMI and long-term mortality. Recently, it has been suggested that even minor postprocedural elevation of TnI is associated with a subsequent increase in cardiovascular risk. Therefore, we presume that prevention of myocardial injury would improve the long-term PCI outcome. Results from several randomized trials have demonstrated that both statin-naive patients and patients on long-term statin therapy assigned to pretreatment with a high dose of atorvastatin or rosuvastatin were associated with a reduced occurrence of myocardial injury or PMI, resulting in better short-term outcomes. However, according to further studies, the effect of statins on the incidence of biomarker release remains controversial. The purpose of this study was to investigate the effect of a 1-day rosuvastatin therapy on TnI release in nonemergency patients admitted for coronary angiography (CAG) and subsequently treated by PCI.


Methods


The TIP 3 study (rosuvasTatin pretreatment Influences the risk of Percutaneous coronary intervention) was a multicenter, international, and randomized study performed in 4 cardiovascular centers in 2 countries between May 2010 and June 2012.


A total of 1,752 patients with stable and TnI-negative coronary artery disease underwent CAG; 445 patients with a de novo lesion >50% indicated for PCI were enrolled and randomized (ratio 1:1) to loading therapy with rosuvastatin (20 mg 12 hours before PCI + 20 mg immediately before PCI; rosuvastatin group; 220 patients) or PCI without loading statin therapy (control group; 225 patients). Patients were randomized independently of their lipid levels, level of C-reactive protein (CRP), and presence or absence of long-term statin therapy. In patients taking statins, rosuvastatin was added to their long-term statin therapy. Blood samples for TnI measurements (Architect, Abbott, Illinois) were taken immediately before PCI, 6 to 12 hours, and 16 to 24 hours thereafter. Additional samples of biomarkers were obtained if the patient developed elevated post-PCI TnI level. The high-sensitivity CRP level (WACO Pure Chemical Industries, Osaka, Japan) was measured at admission, which was 1 day before CAG examination. According to baseline CRP levels taken before loading rosuvastatin therapy, patients were divided into 2 groups (≥2 mg/L or <2 mg/L) to assess the influence of rosuvastatin loading therapy on post-PCI TnI release in relation with a minor CRP elevation. Similarly, patients were divided into 3 groups according to long-term statin therapy to assess its influence on the incidence of post-PCI TnI microleak. The first group comprised patients without statin therapy, the second group comprised patients with long-term low-dose statin therapy (atorvastatin 10 mg, atorvastatin 20 mg, fluvastatin 20 mg, lovastatin 20 mg, rosuvastatin 10 mg, simvastatin 10 mg, simvastatin 20 mg, and simvastatin 40 mg), and the third group comprised patients with long-term high-dose statin therapy (atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin 20 mg, and rosuvastatin 40 mg).


All study protocols were approved by the local ethics committee, and all patients provided written informed consent. The study was registered at ClinicalTrials.gov ( ClinicalTrials.gov ; identifier: NCT01378715 ).


Coronary intervention was performed immediately after CAG. All patients received 100 mg of aspirin and 300 mg of clopidogrel 1 day before PCI. After PCI, aspirin (100 mg/d), clopidogrel (75 mg/d), and statins were prescribed to all the patients.


The primary end point was the peak TnI concentration ≥1.5 times the upper limit of normal (ULN; “TnI microleak”) up to 24 hours after PCI. The secondary end point was the TnI concentration ≥3 times the ULN. Because the last definition of myocardial infarction was published after termination of our study in 2012, we also evaluated the incidence of post-PCI TnI level ≥5 times the ULN, which is a new definition of periprocedural myocardial infarction (PMI). Angiographic success of PCI was defined as residual diameter stenosis <20%, determined by a visual estimation and Thrombolysis in Myocardial Infarction flow grade 3.


The sample size (220 vs 220 patients) was based on previous studies to demonstrate a reduction in the primary end point from 33% in the control group to 20% in the rosuvastatin group (2-sided chi-square test, α = 0.05, power = 0.87). Continuous variables are expressed as mean ± SD or medians with interquartile range; discrete variables are expressed as counts and percentages. The data were tested for normal distribution using the Kolmogorov-Smirnov test. Differences between groups were tested using the chi-square test, Fisher’s exact test, or Mann-Whitney U test as appropriate. Odds ratios and 95% confidence intervals assessing the risk of the primary end point according to potential confounding variables were assessed by logistic regression. The following parameters were evaluated, first in a univariate model: rosuvastatin (re) loading therapy, long-term therapy with β blockers, long-term therapy with statins, multivessel disease, complex lesion (type B2/C vs A/B1), level of total cholesterol and high-density lipoprotein (HDL) cholesterol, symptomatic peripheral atherosclerotic disease, diabetes mellitus, anginal pain at rest, radial approach, gender, and age of the patients. Variables with a p value <0.15 were then entered into a multivariate analysis, which was performed using a logistic regression to identify predictors of the primary end point. A p value <0.05 was considered statistically significant. The statistical software programs Stata, release 9.2 (Stata Corp. LP, College Station, Texas), and GraphPad PRISM, version 4 (GrafPad Software Inc., La Jolla, California), were used for all analyses.




Results


A total of 445 patients with coronary artery disease were randomized and underwent PCI. Clinical and procedural variables were comparable between both groups of patients ( Table 1 ). Long-term pharmacotherapy of the study population is summarized in Tables 2 and 3 .



Table 1

Baseline patient characteristics


















































































































Variable Rosuvastatin Group (n = 220) Control Group (n = 225) p Value
Age (yrs) (range) 67 ± 9 (38–87) 68 ± 10 (33–88) 0.33
Men 71% 63% 0.08
Body mass index, median (IQR) (kg/m 2 ) 28 (26–32) 29 (27–33) 0.01
Angina pectoris, Canadian Society of Cardiology class 1.7 ± 1.1 1.5 ± 1.2 0.25
Dyspnea, NYHA class 1.6 ± 0.9 1.7 ± 1.1 0.38
Previous myocardial infarction 32% 34% 0.66
Previous coronary bypass 13% 12% 0.48
Previous percutaneous coronary intervention 27% 29% 0.85
Previous stroke 6.4% 6.2% 0.85
Atrial fibrillation 11% 8% 0.29
Current smoker 18% 19% 0.80
Hypertension 84% 88% 0.18
CRP (mg/L), median (IQR) 1.7 (0.7–4.5) 2 (0.9–6) 0.27
Serum creatinine (mmol/L), median (IQR) 84 (71–97) 80 (69–97) 0.14
Total cholesterol >5 mmol/L (>193 mg/dl) 29% 32% 0.55
Total plasma cholesterol (mmol/L; mg/dl) 4.8 ± 3.3; 186 ± 128 4.6 ± 1.2; 178 ± 46 0.78
LDL cholesterol (mmol/L; mg/dl) 2.6 ± 0.9; 101 ± 35 2.7 ± 1.0; 104 ± 39 0.99
HDL cholesterol (mmol/L; mg/dl) 1.1 ± 0.3; 43 ± 12 1.1 ± 0.4; 43 ± 16 0.95
Hypertriglyceridemia >2 mmol/L (>177 mg/dl) 27% 32% 0.22
Plasma triglyceride (mmol/L; mg/dl) 1.8 ± 1.5; 159 ± 133 1.8 ± 1.2; 159 ± 106 0.60
Diabetes mellitus 36% 38% 0.61

IQR = interquartile range; LDL = low-density lipoprotein; NYHA = New York Heart Association.


Table 2

Preprocedural medical therapy





























Variable Rosuvastatin Group (n = 220) (%) Control Group (n = 225) (%) p Value
β blockers 62 70 0.06
Calcium antagonists 28 31 0.43
Angiotensin-converting enzyme inhibitors 49 60 0.03
Angiotensin II receptor blockers 19 19 0.66


Table 3

Long-term statin treatment










































































Variable Rosuvastatin Group (n = 220) (%) Control Group (n = 225) (%) p Value
Atorvastatin 10 mg 8.2 5.8 0.32
Atorvastatin 20 mg 32.3 35.1 0.53
Atorvastatin 40 mg 8.6 10.2 0.57
Atorvastatin 80 mg 4.1 6.7 0.23
Fluvastatin 20 mg 1.8 0.9 0.40
Lovastatin 20 mg 0.5 0.4 0.99
Rosuvastatin 10 mg 0.5 2.7 0.06
Rosuvastatin 20 mg 3.2 5.3 0.26
Rosuvastatin 40 mg 0.5 0.4 0.99
Simvastatin 10 mg 2.7 0.4 0.05
Simvastatin 20 mg 5.5 6.7 0.59
Simvastatin 40 mg 3.2 0.4 0.03
Without statins 28.6 24.9 0.37


Angiographic and procedural characteristics were similar in both groups of patients ( Table 4 ). Troponin I values in both groups are summarized in Figure 1 . The baseline values were 0.01 (0.01 to 0.02) mg/L versus 0.01 (0.01 to 0.02) mg/L (p = 0.83). There were no differences in the incidence of primary or secondary end points between groups ( Table 5 ).



Table 4

Peri-procedural intervention and angiographic characteristics of study population




































































































































































Variable Rosuvastatin Group (n = 220) Control Group (n = 225) p Value
Coronary artery narrowed in
Left anterior descending 39% 40% 0.82
Right 29% 33% 0.37
Left circumflex 27% 25% 0.61
Saphenous vein graft 5% 3% 0.19
Left main 3% 3% 0.73
Percutaneous coronary intervention on more vessels 4% 4% 0.67
1 45% 43% 0.68
2 29% 27% 0.64
3 26% 30% 0.36
Type of coronary lesion
A 11% 12% 0.82
B1 21% 16% 0.27
B2 41% 38% 0.63
C 28% 34% 0.20
In-stent restenosis 9% 7% 0.34
Total occlusion 12% 12% 0.93
Preinterventional stenosis (%) 87 ± 10 90 ± 10 0.99
Postinterventional stenosis (%) 6 ± 20 5 ± 18 0.69
Intracoronary thrombosis 2% 7% 0.54
Number of treated narrowings 1.2 ± 0.4 1.2 ± 0.4 0.94
Stents per patient (n) 1.1 1.2 0.59
Direct stenting 49% 50% 0.74
Mean length of stents (mm) 20 ± 13 20 ± 14 0.90
Angiographic success 96% 96% 0.67
Complete revascularization 63% 60% 0.62
Fluoroscopic time (min), median (IQR) 6.4 (4–10) 7.2 (5–11) 0.02
Inflation time (s), median (IQR) 20 (10–60) 31 (10–48) 0.60
Transient vessel closure 2% 3% 0.79
Major dissection 3% 5% 0.33
Q-wave myocardial infarction within 24 h (n) 0 0 1.0

IQR = interquartile range.

Dec 5, 2016 | Posted by in CARDIOLOGY | Comments Off on Effect of Rosuvastatin Therapy on Troponin I Release Following Percutaneous Coronary Intervention in Nonemergency Patients (from the TIP 3 Study)

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