Thrombus Burden After Thrombectomy or PCI-Alone in STEMI
Thrombus Burden After Thrombectomy or PCI-Alone in STEMI
The TOTAL trial was an international, multicentre, randomized trial of routine thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) compared with PCI-alone in STEMI patients treated with primary PCI (n = 10 732). We enrolled patients presenting with symptoms of myocardial ischaemia lasting for ≥30 min and definite electrocardiographic changes indicating STEMI who were referred for primary PCI and randomized within 12 h of symptom onset as previously described. Participation in the OCT sub-study required restoration of TIMI 2–3 flow after the first device (pre-stent imaging) and/or following stent implantation (post-stent imaging). In patients randomized to PCI-alone, pre-stent imaging could also be performed immediately after wire placement if direct stenting was planned and TIMI 2–3 flow was present. In addition to the exclusion criteria of the TOTAL trial, patients were excluded from the OCT sub-study if they were in cardiogenic shock or had known renal failure. All patients enrolled in the OCT sub-study provided informed consent specific to the sub-study.
Optical coherence tomography imaging was performed using the Ilumien™ OCT system and C7 Dragonfly™ catheter (St Jude Medical, Minnesota, MN, USA). The radio-opaque distal marker of the OCT system was positioned 1–2 cm distal to the target lesion or stent. Contrast was injected either manually or automatically by injector, depending on local practice. The images obtained were reviewed by the operator to ensure adequate image quality. A second and/or third image was obtained if the image quality was sub-optimal. A maximum of three images were be attempted. Acquired OCT images were exported in digital format for offline analysis.
Angiograms of patients enrolled in the OCT sub-study were assessed in a dedicated angiographic core laboratory (Hamilton Health Sciences, Canada) blinded to treatment assignment. Pre-stent angiographic TIMI thrombus burden was assessed at the first injection of the infarct related artery. Quantitative coronary angiographic (QCA) measurements were performed on the culprit lesion before intervention and after stenting (QAngioXA, Medis, Leiden, the Netherlands). Measurements included reference vessel diameter, minimum lumen diameter, lesion length, and diameter stenosis.
Optical coherence tomography image analysis was performed by an independent OCT core laboratory (Heart Hospital, Tampere University Hospital, Finland) blinded to the treatment assignment. Analyses were performed using customized software (OCT Miner, Heart Hospital, Tampere University Hospital, Finland) and a proprietary offline research workstation (St Jude Medical) as previously described. The primary outcome was pre-stent thrombus burden (%) defined as the average of the thrombus area divided by the lumen area over the length of the analysed segment. The secondary outcomes were: pre-stent thrombus volume (in mm); pre-stent quadrants of thrombus (absolute number); pre-stent quadrants of thrombus (mean numbers/mm); pre-stent maximal thrombus area (mm); post-stent atherothrombotic burden (%); post-stent atherothrombotic volume (in mm); and post-stent maximal atherothrombotic area (mm). Sample measurements are shown in Figure 1.
(Enlarge Image)
Figure 1.
Measurement of thrombus burden by OCT in two STEMI patients in TOTAL OCT study. Representative cross-sectional OCT images of a patient with high (22.1%) pre-stent TB (A1–6) and another patient with low (3.4%) pre-stent TB (B1–6). Anatomically matched cross-sections of the culprit artery show the original pre-stent lumen area (Area A) and flow area (Area B) tracings in A1–3 and B1–3 and post-stent modified stent area (Area A) and flow area (Area B) tracings in A4–6 and B4–6. Intraluminal thrombus can be observed in cross sections (denoted by asterisks in A2 and A5) and in the longitudinal view (arrows in A2 and A5). An example of post-stent measurements in case of malapposition is shown in B4. Post-stent atherothrombotic burden was 10.2 and 2.7%, respectively, for patients A and B. OCT, optical coherence tomography, STEMI, ST-elevation myocardial infarction.
Based on data from the first 20 patients enrolled in the TOTAL OCT sub-study, we estimated a control pre-stent thrombus burden of 12% (arithmetic mean) and standard deviation of 11.6% and determined that a sample size of 163 patients would have 84% power to detect a 30% reduction in thrombus burden. Assuming that 80% of patients would have analysable pre-stent imaging, we selected a sample size of 200 patients.
Baseline variables were summarized as mean ± standard deviation for continuous variables, median (25th percentile, 75th percentile) for time variables, and n (%) for categorical variables. Baseline variables were compared between thrombectomy and PCI-alone groups with the Pearson χ test for categorical variables and Wilcoxon two-sample test for continuous variables. No P values were determined when there were fewer than four observations in either group.
All pre- and post-stent values were not normally distributed. These outcomes were transformed to improve normality before statistical analysis. The final estimates were presented on the back-transformed scale. Due to non-normal distributions, geometric means were used to describe central tendency. The geometric means and 95% confidence intervals were presented. The t-test was used for significance testing of the transformed data for all primary and secondary outcomes. Two-sided type I error level was set at 5%. A modified intent-to-treat analysis was performed including all patients with analysable OCT images in their randomized group. Pre-specified subgroup analyses were performed for TIMI thrombus grade ≥4 vs. <4 and TIMI thrombus grade ≥3 vs. <3. Interactions between the treatment effect and subgroups were tested using linear regression models with factors for treatment, subgroup, and interaction. The Wald test was used to test for statistical interaction. The non-parametric Spearman rank correlation coefficient was used to assess the correlation between pre- and post-stent outcomes.
Methods
The TOTAL trial was an international, multicentre, randomized trial of routine thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) compared with PCI-alone in STEMI patients treated with primary PCI (n = 10 732). We enrolled patients presenting with symptoms of myocardial ischaemia lasting for ≥30 min and definite electrocardiographic changes indicating STEMI who were referred for primary PCI and randomized within 12 h of symptom onset as previously described. Participation in the OCT sub-study required restoration of TIMI 2–3 flow after the first device (pre-stent imaging) and/or following stent implantation (post-stent imaging). In patients randomized to PCI-alone, pre-stent imaging could also be performed immediately after wire placement if direct stenting was planned and TIMI 2–3 flow was present. In addition to the exclusion criteria of the TOTAL trial, patients were excluded from the OCT sub-study if they were in cardiogenic shock or had known renal failure. All patients enrolled in the OCT sub-study provided informed consent specific to the sub-study.
Optical Coherence Tomography Imaging
Optical coherence tomography imaging was performed using the Ilumien™ OCT system and C7 Dragonfly™ catheter (St Jude Medical, Minnesota, MN, USA). The radio-opaque distal marker of the OCT system was positioned 1–2 cm distal to the target lesion or stent. Contrast was injected either manually or automatically by injector, depending on local practice. The images obtained were reviewed by the operator to ensure adequate image quality. A second and/or third image was obtained if the image quality was sub-optimal. A maximum of three images were be attempted. Acquired OCT images were exported in digital format for offline analysis.
Angiogram Analysis
Angiograms of patients enrolled in the OCT sub-study were assessed in a dedicated angiographic core laboratory (Hamilton Health Sciences, Canada) blinded to treatment assignment. Pre-stent angiographic TIMI thrombus burden was assessed at the first injection of the infarct related artery. Quantitative coronary angiographic (QCA) measurements were performed on the culprit lesion before intervention and after stenting (QAngioXA, Medis, Leiden, the Netherlands). Measurements included reference vessel diameter, minimum lumen diameter, lesion length, and diameter stenosis.
Optical Coherence Tomography Analysis
Optical coherence tomography image analysis was performed by an independent OCT core laboratory (Heart Hospital, Tampere University Hospital, Finland) blinded to the treatment assignment. Analyses were performed using customized software (OCT Miner, Heart Hospital, Tampere University Hospital, Finland) and a proprietary offline research workstation (St Jude Medical) as previously described. The primary outcome was pre-stent thrombus burden (%) defined as the average of the thrombus area divided by the lumen area over the length of the analysed segment. The secondary outcomes were: pre-stent thrombus volume (in mm); pre-stent quadrants of thrombus (absolute number); pre-stent quadrants of thrombus (mean numbers/mm); pre-stent maximal thrombus area (mm); post-stent atherothrombotic burden (%); post-stent atherothrombotic volume (in mm); and post-stent maximal atherothrombotic area (mm). Sample measurements are shown in Figure 1.
(Enlarge Image)
Figure 1.
Measurement of thrombus burden by OCT in two STEMI patients in TOTAL OCT study. Representative cross-sectional OCT images of a patient with high (22.1%) pre-stent TB (A1–6) and another patient with low (3.4%) pre-stent TB (B1–6). Anatomically matched cross-sections of the culprit artery show the original pre-stent lumen area (Area A) and flow area (Area B) tracings in A1–3 and B1–3 and post-stent modified stent area (Area A) and flow area (Area B) tracings in A4–6 and B4–6. Intraluminal thrombus can be observed in cross sections (denoted by asterisks in A2 and A5) and in the longitudinal view (arrows in A2 and A5). An example of post-stent measurements in case of malapposition is shown in B4. Post-stent atherothrombotic burden was 10.2 and 2.7%, respectively, for patients A and B. OCT, optical coherence tomography, STEMI, ST-elevation myocardial infarction.
Statistics
Based on data from the first 20 patients enrolled in the TOTAL OCT sub-study, we estimated a control pre-stent thrombus burden of 12% (arithmetic mean) and standard deviation of 11.6% and determined that a sample size of 163 patients would have 84% power to detect a 30% reduction in thrombus burden. Assuming that 80% of patients would have analysable pre-stent imaging, we selected a sample size of 200 patients.
Baseline variables were summarized as mean ± standard deviation for continuous variables, median (25th percentile, 75th percentile) for time variables, and n (%) for categorical variables. Baseline variables were compared between thrombectomy and PCI-alone groups with the Pearson χ test for categorical variables and Wilcoxon two-sample test for continuous variables. No P values were determined when there were fewer than four observations in either group.
All pre- and post-stent values were not normally distributed. These outcomes were transformed to improve normality before statistical analysis. The final estimates were presented on the back-transformed scale. Due to non-normal distributions, geometric means were used to describe central tendency. The geometric means and 95% confidence intervals were presented. The t-test was used for significance testing of the transformed data for all primary and secondary outcomes. Two-sided type I error level was set at 5%. A modified intent-to-treat analysis was performed including all patients with analysable OCT images in their randomized group. Pre-specified subgroup analyses were performed for TIMI thrombus grade ≥4 vs. <4 and TIMI thrombus grade ≥3 vs. <3. Interactions between the treatment effect and subgroups were tested using linear regression models with factors for treatment, subgroup, and interaction. The Wald test was used to test for statistical interaction. The non-parametric Spearman rank correlation coefficient was used to assess the correlation between pre- and post-stent outcomes.
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