Abstract
The aim was to assess the impact of the short-term anti-inflammatory therapy on coronary endothelial function in non-ST-segment elevation acute coronary syndrome patients. In 30 patients, coronary endothelial function was assessed by acetylcholine test. Vessel response was calculated as a percent change of mean lumen diameter (MLD). Then patients were randomized into three groups: A ( n =11) placebo, B ( n =11) 80 mg atorvastatin, C ( n =8) 80 mg atorvastatin and 25 mg rofecoxib. After 7 days control test was performed. Recovery of coronary endothelial function was calculated as delta in percent changes of MLD between Days 1 and 7. On Day 1, percent change of MLD between baseline and maximum acetylcholine did not differentiate the groups: −20±3.5% in A, −25±3.9% in B and −26±3.7% in C, P =.20. On Day 7, percentage changes in MLD were as follows: −21±3.9% in A, −15±3.0% in B and −10±4.0% in C, P =.002. The delta in percentage change in MLD between Days 1 and 7 were as follows: −1% in A, + 10% in B and +16% in C, P =.02. In conclusion, short-term, anti-inflammatory therapy with high-dose atorvastatin and selective cyclooxygenase-2 inhibitor improves coronary endothelial function within 7 days in non-ST-segment elevation acute coronary syndrome patients.
1
Introduction
The vascular endothelium plays a key role in the pathogenesis of atherosclerosis. Endothelial dysfunction is considered as an important, early marker for atherosclerosis, preceding atherosclerotic plaques formation . Endothelial dysfunction is also an important predictor of serious cardiovascular events in patients with confirmed coronary artery disease (CAD) and without previous clinical manifestation of CAD . Inflammation plays a crucial role in inducing endothelial dysfunction and the progression of atherosclerosis . Acute coronary syndromes (ACS) are associated with a more pronounced inflammatory activity and this response is reflected by elevated levels of systemic inflammatory markers, like C-reactive protein (CRP). Moreover, the persistence of elevated markers is a predictor of poorer outcome in patients with CAD .
Statins have well documented pleiotropic activity (including anti-inflammatory) in patients with CAD . Due to very important role of inflammation in ACS it may be a rationale for targeting inflammatory process with novel drugs which, by adding additional anti-inflammatory activity, will reduce inflammatory process and improve endothelial function.
Cyclooxygenases convert arachidonic acid to eicosanoids that play crucial role in vascular patohysiology (prostacyclin, thromboxane A2 etc). Cyclooxygenase-2 (COX-2), the inducible form of the enzyme, is preferably expressed in atherosclerotic vessels witch rise the concept that COX-2 may strongly contribute to vascular inflammation and atherosclerosis . Based on this background it has been hypothesized that COX-2 inhibitors, such us rofecoxib, could suppress vascular inflammation and finally improved endothelial function.
The purpose of the present study was to assess the effects of short-term, aggressive anti-inflammatory therapy (high-dose statin and selective COX-2 inhibitor) on endothelial function in patients with non-ST-segment elevation ACS (NSTEACS).
2
Methods
2.1
Study population
The study protocol and execution complied with the Declaration of Helsinki and has been approved by the Jagiellonian University Bioethics Committee in Krakow, Poland. All patients gave informed consent to participate in the study. In this prospective, randomized, placebo-controlled study, a total of 30 NSTEACS patients qualifying for invasive treatment were enrolled. The inclusion criteria were: age 18–75 years, NSTEACS as the first manifestation of CAD, elevated CRP >3 mg/l, and absence of contraindications for invasive treatment. Exclusion criteria were as follows: need of urgent percutaneous coronary intervention (PCI), current treatment with statins or anti-inflammatory drugs, confirmed inflammatory disease (rheumatoid arthritis, etc.), prior PCI or coronary artery bypass grafting, angiographic evidence of critical left main stenosis or multivessel disease, left ventricular ejection fraction ≤40%, renal failure, liver failure, and pregnancy.
2.2
Treatment and study procedures
At baseline, all patients underwent coronary angiography and baseline acetylcholine (Ach) test within non-culprit coronary artery. Then patients were randomized into the three therapeutic groups based on computer generated sequence: Group A ( n =11) receiving placebo, Group B ( n =11) receiving atorvastatin (80 mg once daily), and group C ( n =8) receiving atorvastatin (80 mg once daily) and a selective COX-2 inhibitor rofecoxib (25 mg once daily). Number of patients in group C is lower due to sooner withdrawal of rofecoxib from the market. From this time randomization was continued in two groups. The treatment was continued for 7 days. All patients received the standard treatment with aspirin (75 mg once daily), clopidogrel (75 mg once daily), enoxaparin (1 mg per kg of body mass twice daily), and beta-blocker. Angiotensin-converting enzyme inhibitors and calcium channel blockers were not administered during study period. Patients remained under observation in cardiac care unit with 24/7 access to catheterization laboratory. The Ach test was repeated on the Day 7 of the treatment.
2.3
Evaluation of endothelial function
Endothelial function was assessed by Ach test with the same methodology like in ENCORE I Study . The physician who performed Ach test was blinded as to treatment assignment. Ach was infused into the coronary artery with a diameter stenosis ≤40% based on quantitative coronary angiography (QCA), in the bed of the left coronary artery (left anterior descending artery or circumflex artery). Ach was given in graded concentrations of 2×10 −6 , 2×10 −5 , and 1×10 −4 mmol/l. The vasomotor response was measured using QCA at baseline and after each dose of Ach in the same artery segment that was identified on the basis of the anatomical landmarks. Angiographic parameters were analyzed in an independent Core Angiographic Laboratory (Krakow Cardiovascular Research Institute, Poland) using the NewQuant32 software (Sanders Data Systems, Palo Alto, CA, USA) by analysts blinded as to clinical and treatment data. Mean lumen diameter (MLD) was the main parameter in angiographic analysis. The percentage difference in MLD between baseline and after maximal Ach dose reflected the degree of endothelial dysfunction.
Recovery of endothelial function in all groups was calculated as delta in percentage changes of MLD between Days 1 and 7. Hemodynamic parameters and electrocardiogram were monitored during the test in all patients. Non-endothelial dependent vasomotor response was assessed by intracoronary infusion of nitroglycerin at a dose of 200 μg.
2.4
Evaluation of biochemical parameters
Inflammatory markers levels: CRP, fibrinogen, interleukin (IL)-6 and IL-18 were measured in all patients at Days 1 and 7. CRP concentrations were measured by the high sensitivity assay (Dade Behring, Hamburg, Germany) with the detection limit 0.05 mg/dl. Fibrinogen levels were analyzed by rate nephelometry with Beckman array protein system (Beckman Instruments Inc, Paris, France). Measurements of plasma levels of IL-6 (sensitivity 0.039 pg/ml) and IL-18 (sensitivity 12.5 pg/ml) were performed using a commercial enzyme-linked immunosorbent assay (Quantikine, R&D Systems, Abingdon, UK).
2.5
Statistical analysis
Data were analyzed according to the established standards of descriptive statistics. Continuous variables were expressed as mean±S.D. Categorical variables were presented as number (percentage) of patients. Statistical comparisons between groups were performed using chi-square test and Fisher’s exact test for categorical variables and Kruskal-Wallis test for continuous variables, as appropriate. Significance of changes in MLD, CRP, fibrinogen, IL-6 and IL-18 level between Days 1 Day 7 was assessed by Student t test for dependent samples. All tests were two tailed, and a P value of <.05 was considered statistically significant. All statistical analyses were performed using STATISTICA 6.0 Software (Statsoft, Tusla, OK, USA).
2
Methods
2.1
Study population
The study protocol and execution complied with the Declaration of Helsinki and has been approved by the Jagiellonian University Bioethics Committee in Krakow, Poland. All patients gave informed consent to participate in the study. In this prospective, randomized, placebo-controlled study, a total of 30 NSTEACS patients qualifying for invasive treatment were enrolled. The inclusion criteria were: age 18–75 years, NSTEACS as the first manifestation of CAD, elevated CRP >3 mg/l, and absence of contraindications for invasive treatment. Exclusion criteria were as follows: need of urgent percutaneous coronary intervention (PCI), current treatment with statins or anti-inflammatory drugs, confirmed inflammatory disease (rheumatoid arthritis, etc.), prior PCI or coronary artery bypass grafting, angiographic evidence of critical left main stenosis or multivessel disease, left ventricular ejection fraction ≤40%, renal failure, liver failure, and pregnancy.
2.2
Treatment and study procedures
At baseline, all patients underwent coronary angiography and baseline acetylcholine (Ach) test within non-culprit coronary artery. Then patients were randomized into the three therapeutic groups based on computer generated sequence: Group A ( n =11) receiving placebo, Group B ( n =11) receiving atorvastatin (80 mg once daily), and group C ( n =8) receiving atorvastatin (80 mg once daily) and a selective COX-2 inhibitor rofecoxib (25 mg once daily). Number of patients in group C is lower due to sooner withdrawal of rofecoxib from the market. From this time randomization was continued in two groups. The treatment was continued for 7 days. All patients received the standard treatment with aspirin (75 mg once daily), clopidogrel (75 mg once daily), enoxaparin (1 mg per kg of body mass twice daily), and beta-blocker. Angiotensin-converting enzyme inhibitors and calcium channel blockers were not administered during study period. Patients remained under observation in cardiac care unit with 24/7 access to catheterization laboratory. The Ach test was repeated on the Day 7 of the treatment.
2.3
Evaluation of endothelial function
Endothelial function was assessed by Ach test with the same methodology like in ENCORE I Study . The physician who performed Ach test was blinded as to treatment assignment. Ach was infused into the coronary artery with a diameter stenosis ≤40% based on quantitative coronary angiography (QCA), in the bed of the left coronary artery (left anterior descending artery or circumflex artery). Ach was given in graded concentrations of 2×10 −6 , 2×10 −5 , and 1×10 −4 mmol/l. The vasomotor response was measured using QCA at baseline and after each dose of Ach in the same artery segment that was identified on the basis of the anatomical landmarks. Angiographic parameters were analyzed in an independent Core Angiographic Laboratory (Krakow Cardiovascular Research Institute, Poland) using the NewQuant32 software (Sanders Data Systems, Palo Alto, CA, USA) by analysts blinded as to clinical and treatment data. Mean lumen diameter (MLD) was the main parameter in angiographic analysis. The percentage difference in MLD between baseline and after maximal Ach dose reflected the degree of endothelial dysfunction.
Recovery of endothelial function in all groups was calculated as delta in percentage changes of MLD between Days 1 and 7. Hemodynamic parameters and electrocardiogram were monitored during the test in all patients. Non-endothelial dependent vasomotor response was assessed by intracoronary infusion of nitroglycerin at a dose of 200 μg.
2.4
Evaluation of biochemical parameters
Inflammatory markers levels: CRP, fibrinogen, interleukin (IL)-6 and IL-18 were measured in all patients at Days 1 and 7. CRP concentrations were measured by the high sensitivity assay (Dade Behring, Hamburg, Germany) with the detection limit 0.05 mg/dl. Fibrinogen levels were analyzed by rate nephelometry with Beckman array protein system (Beckman Instruments Inc, Paris, France). Measurements of plasma levels of IL-6 (sensitivity 0.039 pg/ml) and IL-18 (sensitivity 12.5 pg/ml) were performed using a commercial enzyme-linked immunosorbent assay (Quantikine, R&D Systems, Abingdon, UK).
2.5
Statistical analysis
Data were analyzed according to the established standards of descriptive statistics. Continuous variables were expressed as mean±S.D. Categorical variables were presented as number (percentage) of patients. Statistical comparisons between groups were performed using chi-square test and Fisher’s exact test for categorical variables and Kruskal-Wallis test for continuous variables, as appropriate. Significance of changes in MLD, CRP, fibrinogen, IL-6 and IL-18 level between Days 1 Day 7 was assessed by Student t test for dependent samples. All tests were two tailed, and a P value of <.05 was considered statistically significant. All statistical analyses were performed using STATISTICA 6.0 Software (Statsoft, Tusla, OK, USA).
3
Results
A total of 30 patients were enrolled in the study and were randomized into three groups. There was no difference in baseline demographic and clinical characteristics of patients ( Table 1 ) and biochemical markers levels at Day 1 ( Table 2 ) between study groups.
| Variable | Group A placebo ( n =11) | Group B statin ( n =11) | Group C statin+COX-2 inhibitor ( n =8) |
|---|---|---|---|
| Male | 8 (72.7) | 7 (63.6) | 6 (75) |
| Age (years) | 59±9.3 | 55±15 | 60.0±14 |
| Body mass index (kg/m 2 ) | 27.6±5.7 | 26.7±3.7 | 26.2±2.5 |
| Diabetes mellitus | 1 (9.1) | 1 (9.1) | 1 (12.5) |
| Arterial hypertension | 5 (45.5) | 6 (54.5) | 4 (50) |
| Current smoker | 4 (36.4) | 5 (45.5) | 3 (37.5) |
| Family history of coronary artery disease | 5 (45.5) | 4 (36.4) | 3 (37.5) |
| Left ventricular ejection fraction (%) | 56±9.3 | 54±7.8 | 59±5.5 |
| Systolic blood pressure on admission (mmHg) | 137±14 | 142±11 | 141±11 |
| Diastolic blood pressure on admission (mmHg) | 80±8 | 81±6 | 79±6 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
