Abstract
Background
The aim of this study was to examine the influence of ezetimibe in addition to atorvastatin on plaque composition in patients with first-time ST-segment Elevation Myocardial Infarction treated with primary percutaneous intervention.
Methods
Eighty-seven patients were randomized (1:1) to ezetimibe 10 mg or placebo in addition to Atorvastatin 80 mg. Intravascular ultrasound with iMap was performed at baseline and after 12 months in a non-infarct-related artery. Primary endpoint was change in necrotic core (NC). Secondary endpoints were total atheroma volume (TAV) and percentage atheroma volume (PAV).
Results
NC did not change significantly: ezetimibe group 24.9 (11.9, 51.3) mm 3 to 24.9 (15.3, 54.5) mm 3 , p = 0.76, placebo group 29.4 (16.3, 78.5) mm 3 to 32.0 (16.0, 88.7) mm 3 , p = 0.30, (p = 0.35 between groups). TAV was reduced in the ezetimibe group only: ezetimibe (200.0 (135.6, 311.9) mm 3 to 189.3 (126.4, 269.1) mm 3 , p < 0.001) compared to placebo group (218.4 (163.5, 307.9) mm 3 to 212.2 (149.9, 394.8) mm 3 , p = 0.07) (p = 0.56 between groups). PAV was reduced in the ezetimibe group only (40.1 ± 8.6% to 39.2 ± 9.0%, p = 0.036) compared to placebo group (43.3 ± 9.4% to 42.2 ± 10.7%, p = 0.07), p = 0.91 between groups.
Conclusions
Ezetimibe in addition to atorvastatin therapy did not influence NC content, but was associated with regression of coronary atherosclerosis.
Highlights
- •
The influence of the cholesterol absorption inhibitor ezetimibe as addition to atorvastatin on coronary plaque composition following ST segment myocardial infarction (STEMI) was assessed using intravascular ultrasound with iMap tissue characterization.
- •
The study was a double-blinded placebo single-center controlled trial enrolling patients with first time STEMI randomizing patients to treatment with either ezetimibe or placebo in addition to high-dose atorvastatin.
- •
Plaque regression was induced in both arms, but no change in iMap plaque composition was found.
1
Introduction
Pathological studies have demonstrated that plaque ruptures are more likely to develop in plaques with a necrotic core covered by a Thin-Cap Fibroatheroma (TCFA) . The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study showed, that future coronary events more often arise in areas characterized by high plaque burden, luminal stenosis, and presence of TCFA .
High-dose statin treatment has been shown to reduce cardiovascular events significantly . A linear relation between LDL reduction and diminished plaque progression assessed by intravascular ultrasound (IVUS) is well established and has been shown to correlate with clinical outcome . Classical greyscale IVUS has been expanded with spectral analysis of radio-frequency data referred to as Virtual Histology (VH-IVUS, Volcano Therapeutics), Integrated Backscatter IVUS (IB-IVUS) and Tissue Characterization with iMap (Boston Scientific). Although these different imaging modalities are related from a technical point of view, various differences do exist and a direct comparison of measurements can therefore not be made . With iMap it is possible to assess the plaque composition in vivo and stratify tissue types into fibrotic (FT), lipidic (LT), calcific (CT), or necrotic subtypes (NC) . Ex vivo validation studies have shown high sensitivity and specificity compared to histological findings . VH-IVUS studies evaluating the effect of potent statins have demonstrated a modest reduction in necrotic core , while other studies have found no change in NC .
Serial IVUS studies have proven that diminished plaque progression correlates with achieved low density lipoprotein (LDL) reduction and that plaque regression was induced when LDL was reduced to below 2.0 mmol/l , but the additional effects on plaque progression of other LDL lowering agents than statins are not well elucidated.
The cholesterol inhibitor ezetimibe has been shown to induce additional LDL-reduction when added to statin treatment . This might potentially lead to an improved plaque regression and composition compared to high-dose statin therapy alone. Recently the impact of dual-lipid lowering therapy with ezetimibe in addition to atorvastatin in patients treated with percutaneous coronary intervention was assessed in the PRECISE-IVUS trial . It was found, that the combination of atorvastatin and ezetimibe resulted in greater coronary plaque regression than atorvastatin monotherapy.
The aim of the present trial was to evaluate the influence of ezetimibe in addition to high-dose atorvastatin on plaque composition after 12 months in statin naïve patients with ST-segment elevation myocardial infarction (STEMI) using iMap.
2
Methods
2.1
Study population
The OCTIVUS trial ( NCT01385631 ) was a single-center double-blinded randomized trial enrolling statin naïve patients with first-time STEMI. The study was approved by the Danish Ethical Committee and the Danish Medical Agency.
From June 2011 to June 2013 a total of 1062 patients were admitted with STEMI, and of these 87 patients were included.
The main inclusion criteria were: (1) first-time STEMI; (2) no prior treatment with statins or other lipid lowering drugs; and (3) a non-significant lesion in one of the two non-culprit coronary arteries (angiographic diameter stenosis >20% and <50%).
The main exclusion criteria were (1) age below 18 or above 81 years; (2) serum creatinine >176 μmol/l; (3) women with child-bearing potential who were not using chemical or mechanical contraception; 4) history of malignancy unless a disease-free period of more than five years was present; (5) participation in another randomized trial; (6) treatment with cyclosporine or fibrates.
All patients provided written, informed consent, and the study was performed in accordance with the rules for good clinical practice (GCP) and monitored by the local GCP-department.
All study patients were re-examined with a supplementary IVUS of a study plaque in a non-infarct related artery. It was intended to investigate the patient the next day after the primary PCI procedure, but during either weekends or holydays, the examination was done at the first coming workday.
The patients were then treated with atorvastatin 80 mg/day and block randomized (1:1) by envelope method to additional ezetimibe 10 mg/day (Merck & Co., Inc., New Jersey, USA) or placebo. The randomization procedure was administered by the hospital pharmacy who also supplied the blinded study medicine. IVUS including iMap was repeated after 1 year.
2.2
IVUS procedure
The IVUS pullback was performed using the iLab System with a mechanical 40 MHz Atlantis SR Pro IVUS catheter (Both Boston Scientific, USA). Unfractionated heparin (5000 IE) was administered prior to the procedure. The catheter position was determined and matched angiographically by visualization of side-branches. Nitroglycerin 200 μg was administered intracoronary prior to the pullback. An automatic pullback was performed with a standard pullback speed of 0.5 mm/s from distally to an angiographic insignificant lesion to the aorta. iMap data was obtained in every 30th frame (0.5 mm) but was unobtainable in very large vessels giving need for deviation from the standard scanning depth of 5 mm.
All recordings were assigned to randomly generated examination ID numbers corresponding to a list managed by a person not involved in the study and archived to DVDs.
2.3
IVUS off-line analysis
IVUS pullbacks were analyzed by a dedicated operator (MH), who was blinded to treatment assignment and temporal sequence of paired examinations. Echoplaque 4.0 (Indec Medical Systems, Santa Clara, CA, USA) was used for analysis. Baseline and follow-up pullbacks were matched to include as much overlapping segment as possible. Side branches were used as anatomical landmarks, and matching was performed using a dual display workstation. Cross sectional area (CSA) for lumen and the external elastic membrane (EEM) were traced manually in every iMap-containing frame, i.e. for every 30th frame (0.5 mm).
To allow for use of guidewire during the study period, the effect of the artifact was determined in 10 patients, who had their study plaque assessed with IVUS and iMap in 4 subsequent pullbacks of the same segment – 2 with and 2 without guidewire. In the off-line analysis of pullbacks over a guidewire, the artifact was both included and manually excluded from the offline iMap quantification. The guidewire artifact was omitted from the iMap analysis by applying special masks within EchoPlaque (“no-fly zones”). At follow-up, pullbacks with guidewire were only performed if the same practice was used at baseline. An example of the iMap assessment is depicted in Fig. 1 .
A volumetric assertion of the 10 mm most diseased segment at baseline was performed with respect to gray scale IVUS measurements and iMap data and the same segment was identified and analyzed at follow-up. Vessel and lumen volume was calculated within EchoPlaque as respectively ∑EEM CSA and ∑LUMEN CSA , where EEM CSA = external elastic membrane cross-sectional area, and LUMEN CSA = luminal cross-sectional area. TAV was defined as vessel volume minus lumen volume, and PAV was defined as (TAV/vessel volume) × 100%. Volumetric iMap data was calculated after definition of lumen, EEM contours, and “no-fly zones”. EchoPlaque 4.0 natively supports iMap data and calculates iMap tissue type contents and their relative contributions automatically, when lumen contours have been defined.
2.4
Endpoint
The primary endpoint was change in the relative NC content after 12 months. Secondary endpoints were change in FT, LT, and CT together with changes in total atheroma volume (TAV) and percentage atheroma volume (PAV).
2.5
Statistical analysis
Statistical analysis was performed with SPSS 21.0 (IBM Corporation, New York, USA). Categorical data are presented as frequencies and percentages and compared using chi-square test. Normal distributed continuous data are presented as mean ± SD and compared using a Student’s t-test or presented as median with inter quartile range (IQR) and compared using the Mann–Whitney U test when normality testing failed. A Shapiro–Wilk test was used together with Q-Q-plots for this assessment. A paired samples t-test or Wilcoxon Matched-Pair Signed-Rank test was used in comparison of changes from baseline to follow-up. A two-sided p-value of <0.05 was considered statistical significant. Linear correlations were tested with Pearson’s correlation and in case of non-linearity, a Spearman correlation was used.
The sample size calculation was based upon an estimation approach, because the effect of atorvastatin in combination with ezetimibe on plaque components was unknown. A change in NC of 25% in the ezetimibe group and 15% in the placebo group with a SD of 16.5% was estimated, alpha error of 0.05, and a power of 80%. Thus, a minimum of 44 patients in each treatment group was pre-specified for enrolment.
2
Methods
2.1
Study population
The OCTIVUS trial ( NCT01385631 ) was a single-center double-blinded randomized trial enrolling statin naïve patients with first-time STEMI. The study was approved by the Danish Ethical Committee and the Danish Medical Agency.
From June 2011 to June 2013 a total of 1062 patients were admitted with STEMI, and of these 87 patients were included.
The main inclusion criteria were: (1) first-time STEMI; (2) no prior treatment with statins or other lipid lowering drugs; and (3) a non-significant lesion in one of the two non-culprit coronary arteries (angiographic diameter stenosis >20% and <50%).
The main exclusion criteria were (1) age below 18 or above 81 years; (2) serum creatinine >176 μmol/l; (3) women with child-bearing potential who were not using chemical or mechanical contraception; 4) history of malignancy unless a disease-free period of more than five years was present; (5) participation in another randomized trial; (6) treatment with cyclosporine or fibrates.
All patients provided written, informed consent, and the study was performed in accordance with the rules for good clinical practice (GCP) and monitored by the local GCP-department.
All study patients were re-examined with a supplementary IVUS of a study plaque in a non-infarct related artery. It was intended to investigate the patient the next day after the primary PCI procedure, but during either weekends or holydays, the examination was done at the first coming workday.
The patients were then treated with atorvastatin 80 mg/day and block randomized (1:1) by envelope method to additional ezetimibe 10 mg/day (Merck & Co., Inc., New Jersey, USA) or placebo. The randomization procedure was administered by the hospital pharmacy who also supplied the blinded study medicine. IVUS including iMap was repeated after 1 year.
2.2
IVUS procedure
The IVUS pullback was performed using the iLab System with a mechanical 40 MHz Atlantis SR Pro IVUS catheter (Both Boston Scientific, USA). Unfractionated heparin (5000 IE) was administered prior to the procedure. The catheter position was determined and matched angiographically by visualization of side-branches. Nitroglycerin 200 μg was administered intracoronary prior to the pullback. An automatic pullback was performed with a standard pullback speed of 0.5 mm/s from distally to an angiographic insignificant lesion to the aorta. iMap data was obtained in every 30th frame (0.5 mm) but was unobtainable in very large vessels giving need for deviation from the standard scanning depth of 5 mm.
All recordings were assigned to randomly generated examination ID numbers corresponding to a list managed by a person not involved in the study and archived to DVDs.
2.3
IVUS off-line analysis
IVUS pullbacks were analyzed by a dedicated operator (MH), who was blinded to treatment assignment and temporal sequence of paired examinations. Echoplaque 4.0 (Indec Medical Systems, Santa Clara, CA, USA) was used for analysis. Baseline and follow-up pullbacks were matched to include as much overlapping segment as possible. Side branches were used as anatomical landmarks, and matching was performed using a dual display workstation. Cross sectional area (CSA) for lumen and the external elastic membrane (EEM) were traced manually in every iMap-containing frame, i.e. for every 30th frame (0.5 mm).
To allow for use of guidewire during the study period, the effect of the artifact was determined in 10 patients, who had their study plaque assessed with IVUS and iMap in 4 subsequent pullbacks of the same segment – 2 with and 2 without guidewire. In the off-line analysis of pullbacks over a guidewire, the artifact was both included and manually excluded from the offline iMap quantification. The guidewire artifact was omitted from the iMap analysis by applying special masks within EchoPlaque (“no-fly zones”). At follow-up, pullbacks with guidewire were only performed if the same practice was used at baseline. An example of the iMap assessment is depicted in Fig. 1 .
A volumetric assertion of the 10 mm most diseased segment at baseline was performed with respect to gray scale IVUS measurements and iMap data and the same segment was identified and analyzed at follow-up. Vessel and lumen volume was calculated within EchoPlaque as respectively ∑EEM CSA and ∑LUMEN CSA , where EEM CSA = external elastic membrane cross-sectional area, and LUMEN CSA = luminal cross-sectional area. TAV was defined as vessel volume minus lumen volume, and PAV was defined as (TAV/vessel volume) × 100%. Volumetric iMap data was calculated after definition of lumen, EEM contours, and “no-fly zones”. EchoPlaque 4.0 natively supports iMap data and calculates iMap tissue type contents and their relative contributions automatically, when lumen contours have been defined.
2.4
Endpoint
The primary endpoint was change in the relative NC content after 12 months. Secondary endpoints were change in FT, LT, and CT together with changes in total atheroma volume (TAV) and percentage atheroma volume (PAV).
2.5
Statistical analysis
Statistical analysis was performed with SPSS 21.0 (IBM Corporation, New York, USA). Categorical data are presented as frequencies and percentages and compared using chi-square test. Normal distributed continuous data are presented as mean ± SD and compared using a Student’s t-test or presented as median with inter quartile range (IQR) and compared using the Mann–Whitney U test when normality testing failed. A Shapiro–Wilk test was used together with Q-Q-plots for this assessment. A paired samples t-test or Wilcoxon Matched-Pair Signed-Rank test was used in comparison of changes from baseline to follow-up. A two-sided p-value of <0.05 was considered statistical significant. Linear correlations were tested with Pearson’s correlation and in case of non-linearity, a Spearman correlation was used.
The sample size calculation was based upon an estimation approach, because the effect of atorvastatin in combination with ezetimibe on plaque components was unknown. A change in NC of 25% in the ezetimibe group and 15% in the placebo group with a SD of 16.5% was estimated, alpha error of 0.05, and a power of 80%. Thus, a minimum of 44 patients in each treatment group was pre-specified for enrolment.
3
Results
3.1
Patient population
Eighty-seven patients were enrolled in the study and assigned to the ezetimibe (n = 43) or placebo (n = 44) treatment arms on top of treatment with atorvastatin 80 mg. Mean time from primary PCI to IVUS of a study lesion in a non-infarct related artery was 29.3 ± 16.5 h. Baseline examinations failed for 1 person. Four patients were lost to invasive follow-up (1 patient died of sudden cardiac arrest, 1 patient died of pulmonary cancer found after baseline examination, 1 patient got a disseminated cancer, and 1 patient withdrew consent). In 5 patients, either baseline or follow-up IVUS of the target vessel could not be achieved or was unsuitable for analysis. The mean follow-up time was 353 ± 14 days in the ezetimibe group and 356 ± 13 days in the placebo group (p = ns). Seventy-seven patients completed IVUS follow-up, but iMap data was only available in 66 patients (iMap data in 3 patients was lost during export to DVD, in 3 patients adjustment to the scanning depth was done, and in the remaining 6 patients, iMap data was not processed prior to export as a result of a system upgrade).
Baseline characteristics are listed in Table 1 . The two groups were well balanced. Two patients in the ezetimibe group had suspected adverse advents to atorvastatin: One patient was changed to low-dose rosuvastatin after 3 months due to elevated liver enzymes, another patient discontinued atorvastatin due to worsening of a pre-existing rheumatic condition. In one patient in the placebo group, the statin treatment was unintentionally changed to simvastatin 40 mg by the local hospital prior to initial discharge and the patient continued on that treatment. All patients were maintained in their designated treatment arm for the analysis in concordance with intention to treat.
| Ezetimibe (n = 43) | Placebo (n = 44) | p | |
|---|---|---|---|
| Age, years | 55.3 ± 11.0 | 57.2 ± 9.1 | 0.38 |
| Male gender, n (%) | 39 (90.7) | 36 (81.8) | 0.23 |
| Hypertension, n (%) | 7 (16.3) | 8 (18.2) | 0.81 |
| Current smoking, n (%) | 25 (58.1) | 23 (52.3) | 0.74 |
| Family disposition, n (%) | 19 (44.2) | 22 (50.0) | 0.59 |
| Diabetes, n (%) | 1 (2.3) | 1 (2.3) | 0.99 |
| Total Cholesterol >5 mmol/l, n (%) | 32 (74.4) | 30 (68.2) | 0.64 |
| HbA1c (mmol/mol) | 39.0 (36.0, 41.0) | 37.0 (36.0, 41.0) | 0.98 |
| Systolic blood pressure, mmHg | 129.7 ± 21.4 | 125.0 ± 19.8 | 0.29 |
| Diastolic blood pressure, mmHg | 78.1 ± 18.2 | 75.1 ± 10.2 | 0.34 |
| Heart rate, beats/min | 71.0 (60.0, 83.0) | 68.0 (60.0, 81.5) | 0.62 |
| Weight | 86.0 (78.0, 95.0) | 85.0 (76.8, 94.0) | 0.81 |
| BMI (kg/m 2 ) | 27.3 (25.1, 29.2) | 27.4 (24.6, 29.4) | 0.99 |
| LVEF | 50.0 (40.0, 55.0) | 50.0 (45.0, 60.0) | 0.20 |
| Single vessel disease, n (%) | 33 (76.7) | 29 (65.9) | 0.43 |
| Infarct related artery, n (%) | 0.11 | ||
| RCA | 11 (25.6) | 20 (45.5) | |
| LAD | 27 (62.8) | 15 (34.1) | |
| LCx | 5 (11.6) | 9 (20.5) | |
| Study vessel, n (%) | 0.07 | ||
| RCA | 16 (37.2) | 11 (25.0) | |
| LAD | 12 (27.9) | 23 (52.3) | |
| LCx | 15 (34.9) | 10 (22.7) | |
| Prior cardiovascular medications, n (%) | |||
| β-Blockers | 0 (0.0) | 2 (4.5) | 0.16 |
| Calcium antagonists | 4 (9.3) | 3 (6.8) | 0.67 |
| ACE inhibitors | 4 (9.3) | 3 (6.8) | 0.67 |
| ATII inhibitors | 0 (0.0) | 1 (2.3) | 0.32 |
| Diuretics | 1 (2.3) | 3 (6.8) | 0.32 |
| Guidewire used during pullbacks, n (%) | 0.81 | ||
| Present | 27 (69.2) | 26 (66.7) | |
| Not present | 12 (30.8) | 13 (33.3) |
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