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Left Ventricular Remodeling After Anterior-STEMI PCI: Imaging Observations in the Door-to-Unload (DTU) Pilot Trial
Abstract
Objectives. To determine the predictive value of cardiac magnetic resonance (CMR) and echocardiographic parameters on left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients without cardiogenic shock and treated with mechanical LV unloading followed by immediate or delayed percutaneous coronary intervention (PCI)-mediated reperfusion. Background. In STEMI, infarct size (IS) directly correlates with major cardiovascular outcomes. Preclinical models demonstrate mechanical LV unloading before reperfusion reduces IS. The door-to-unload (DTU)-STEMI pilot trial evaluated the safety and feasibility of LV unloading and delayed reperfusion in patients with STEMI. Methods. This multicenter, prospective, randomized, safety and feasibility trial evaluated patients with anterior STEMI randomized 1:1 to LV unloading with the Impella CP (Abiomed) followed by immediate reperfusion vs delayed reperfusion after 30 minutes of unloading. Patients were assessed by CMR at 3-5 days and 30 days post PCI. Echocardiographic evaluations were performed at 3-5 and 90 days post PCI. At 3-5 days post PCI, patients were compared based on IS as percentage of LV mass (group 1 ≤25%, group 2 >25%). Selection of IS threshold was performed post hoc. Results. Fifty patients were enrolled from April 2017 to May 2018. At 90 days, group 1 (IS ≤25%) exhibited improved LV ejection fraction (from 53.1% to 58.9%; P=.001) and group 2 (IS >25%) demonstrated no improvement (from 37.6% to 39.1%; P=.55). LV end-diastolic volume and end-systolic volume were unchanged in group 1 and worsened in group 2. There was correlation between 3-5 day and 30-day CMR measurements of IS and 90-day echocardiography-derived LV ejection fraction. Conclusions. Immediate 3-5 day post-therapy IS by CMR correlates with 90-day echocardiographic LVEF and indices of remodeling. Patients with post-therapy IS >25% demonstrated evidence of adverse remodeling. Larger studies are needed to corroborate these findings with implications on patient management and prognosis.
Keywords: CMR, infarct size, STEMI, unloading, imaging, remodeling
Timely myocardial reperfusion with percutaneous coronary intervention (PCI) has resulted in major mortality reduction in patients with non-shock ST-segment elevation myocardial infarction (STEMI).1,2 Despite this mortality reduction, a large proportion of patients survive with impaired ventricular function.3 Long term, this results in adverse cardiac remodeling, increased risk of sudden cardiac death, and the development of ischemic cardiomyopathy.4,5 In addition to total duration of ischemia, anterior MI location has been shown to directly impact final infarction size (IS).6 Stone et al have shown that patients with anterior MI have time dependency for myocardial salvage for the first 180 minutes of symptom duration.7 After this, myocardial infarct size is modified by a variety of factors, including baseline TIMI flow, extent of collaterals, antecedent angina, and afterload. To date, results from efforts to further modify IS have been disappointing.8
Over the past 2 decades, numerous preclinical studies have shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) prior to coronary reperfusion reduces myocardial injury and IS.9-11 More recent studies have demonstrated that LV unloading and delaying reperfusion by 30 minutes activates cardioprotective signaling cascades that promote myocardial recovery 30 days post infarction.12,13 These findings suggest that unloading before reperfusion is feasible and may offer a new approach to reduce IS and to lower the incidence of heart failure (HF) and mortality after STEMI. Since a delay in reperfusion could result in more extensive IS, a pilot safety and feasibility study is required.
The DTU-STEMI (Door-to-Unload in STEMI) pilot trial was the first exploratory study to assess the safety and feasibility of LV unloading before reperfusion using the Impella CP (Abiomed, Inc) prior to the conduction of a large pivotal trial (the STEMI-DTU study; NCT03947619), which is now underway.14 The percutaneously delivered hemodynamic support device reduces myocardial oxygen demand and is clinically indicated for high-risk coronary intervention and cardiogenic shock.15-17 The ability to safely delay reperfusion may permit the administration of adjunct therapies during the unloaded period where the coronary artery remains occluded, which may further reduce IS, HF, and mortality. We report the imaging results of the DTU-STEMI randomized feasibility study.
Methods
Trial design and study population. The DTU-STEMI pilot trial study design, population, procedures, endpoints, and results have been previously described.14 In brief, the DTU-STEMI pilot trial was a prospective, multicenter, randomized pilot trial that enrolled patients at 14 centers in the United States and was designed to explore the feasibility and safety of mechanical unloading before coronary reperfusion in patients presenting with anterior STEMI. Patients presenting with STEMI within 1-6 hours from symptom onset were randomly assigned to 1 of 2 treatment arms: (1) LV unloading with the Impella CP system followed by immediate reperfusion (U-IR); or (2) LV unloading with a 30-minute delay to reperfusion (U-DR). This comparison was designed to test whether unloading the myocardium for 30 minutes before reperfusion was feasible, or safe, and if delaying reperfusion increased IS. The current study population represents a subgroup of the DTU-STEMI pilot trial population with available cardiac magnetic resonance (CMR) imaging data.
Outcome measures. The primary safety outcome was the composite of major cardiovascular and cerebrovascular event (MACCE) rate at 30 days. Efficacy measures included IS, LV volumes, and LV ejection fraction (LVEF) by CMR at 3-5 days and at 30 days post PCI. Measurements of LV volumes, LVEF, and anterior regional wall motion were evaluated by echocardiography (echo) at 3-5 days and 90 days post PCI. In this post hoc analysis, patients were further divided into 2 groups based on IS measured at days 3-5 post PCI (group 1, IS ≤25% LV mass; group 2, IS >25% LV mass).
Institutional review boards at each site approved the trial and all patients provided written informed consent. Angiographic, CMR, echo, and electrocardiographic studies were analyzed by core laboratories blinded to the treatment allocation. The study design was approved by the United States Food and Drug Administration and registered accordingly (NCT03000270). All data and materials of this study will not be made available to other researchers outside of the coauthors and investigators for the purposes of reproducing the results or replicating the procedure.
Cardiac magnetic resonance. Patients underwent CMR imaging on days 3-5 and again on day 30 (± 7 days). Delayed enhancement imaging was performed using a 2-dimensional sequence, 10 minutes after administration of routine intravenous gadolinium contrast and analyzed for the presence and extent of infarction and microvascular obstruction. Infarct size was expressed as a percentage of total LV mass. A central core laboratory (Duke Cardiovascular Magnetic Resonance Center in Durham, North Carolina) performed quality assessment on the images during the conduct of the study and manually performed assessment of CMR parameters on deidentified images.
Echocardiography. For 2-dimensional LV volumes and LVEF, a protocol-defined image acquisition was performed from an apical 4-chamber and 2-chamber view.18 Foreshortening was avoided by noting that the majority of the papillary muscles were not in view and ensuring that the long axes of the 4- and 2-chamber views were similar (not more than 20% difference). The modified Simpson’s rule or biplane method of disks was used to perform volumetric measurements of the LV by tracing the endocardium at end systole (LVESV) and end diastole (LVEDV) in a 4- and 2-chamber view. Left ventricular ejection fraction was derived by the following formula:
LVEF = (LVEDV – LVESV) / LVEDV
If the length of the 2-chamber and 4-chamber views differed by 20%, then a single plane was used, except in ventricles with extensive myocardial wall motion. Wall motion was scored using a 16-segment model, with each segment being analyzed and scored according to the degree of systolic thickening. Multiple views (4-, 2-, and 3-chamber views of the LV and 3 short-axis views) were obtained to assess wall motion. A 4-grade scoring was applied: (1) normal or hyperkinetic; (2) hypokinetic (reduced thickening); (3) akinetic (absent or negligible thickening); or (4) dyskinetic (systolic thinning or stretching).
Statistical analysis. Post hoc statistical analyses were performed to compare patients in group 1 with those in group 2. All statistical tests and confidence intervals, as appropriate, were performed at α=.05. Two-sided t tests or Fisher’s exact test were performed for baseline characteristics. Paired t tests were used to compare group changes over time. Analyses of changes in measures and correlations between IS measured by CMR at 3-5 days and 30 days and echo-derived measurements 90 days after therapy were performed. Two-sided t tests were used to compare differences between group 1 and group 2 at specific time points.
Results
Between April 2017 and May 2018, a total of 50 patients with anterior STEMI were enrolled and randomly assigned to either the U-IR or U-DR arms (n = 25/group). Baseline patient characteristics, mean procedural time from start of PCI to Impella CP implantation, and timing from device implantation to reperfusion in the U-IR and U-DR groups were as previously described in the DTU-STEMI pilot trial.13,14 All patients assigned to the U-DR arm completed 30 minutes of LV unloading prior to reperfusion. A total of 41 patients had complete 3-5 imaging datasets available for evaluation. One patient was lost to follow-up 3-5 days post intervention and a second patient received a non-contrast CMR, resulting in a total of 39 patients with analyzable CMR imaging data at 30-day and 90-day time points (Figure 1).
CMR was performed in 21/25 U-DR patients (84%) and 20/25 U-IR patients (80%) between days 3 and 5 and in 21/25 U-DR patients (84%) and 19/25 U-IR patients (76%) at 30-day follow-up. The primary efficacy endpoint of IS normalized to total LV mass at 30 days occurred in 40/50 patients (14.1%) for the total group, with no difference observed between treatment arms (U-DR 13.1 ± 11.3% vs U-IR 15.3 ± 11.5%; P=.53).
Post hoc imaging analysis was performed to evaluate the 39 patients based on IS. Tertile 1 represented IS <10% (n = 14), tertile 2 represented IS ≥10% to ≤25% (n = 13), and tertile 3 represented IS >25% (n = 12). Tertiles 1 and 2 behaved similarly in all analyses and were pooled into the same group, hereafter referred to as group 1 (IS ≤25%; n = 27). Group 2 included those patients with an IS >25% (n = 12).
Patient characteristics. Of the 39 patients with available imaging data, group 1 (patients with IS ≤25%) had a higher percentage of patients than group 2 (59% [n = 27] vs 33.3% [n = 12], respectively; P=.18) (Table 1). The average age was similar between groups (57 ± 11 years in group 1 vs 61 ± 9 years in group 2; P=.26), with the majority of patients being male (74% in group 1 vs 83% in group 2; P=.69). Baseline mean LVEDP in group 1 was lower than in group 2 (22.1 mm Hg vs 28.3 mm Hg; P=.05). Anterior ST elevation sum (ΣSTE) was lower in group 1 than group 2 (9.2 ± 5.3 mm vs 12.6 ± 6.1 mm; P=.11), without statistical significance. The percentage of patients in each group with ΣSTE >6 was lower in patients with IS ≤25% (group 1 = 70.4%) than in patients with IS >25% (group 2 = 91.7%) without statistical significance (Table 1).
Procedural timing analysis. Procedural duration analysis was evaluated by time in minutes utilizing multiple parameters (Table 1). Door-to-balloon time was comparable between group 1 and group 2 (84 ± 27 minutes vs 75 ± 23 minutes; P=.27) (Table 1). Time between patient symptom onset to mechanical unloading was comparable between group 1 and group 2 (209 ± 151 minutes vs 154 ± 63 minutes; P=.12). Time between patient symptom onset to balloon time was also comparable between group 1 and group 2 (237 ± 149 minutes vs 174 ± 68 minutes; P=.08) (Table 1). Lastly, no differences were observed in mechanical unloading to coronary angiography time between group 1 and group 2 (10 ± 10 minutes vs 8 ± 12 minutes; P=.62) or mechanical unloading to coronary balloon time between group 1 and group 2 (23 ± 13 minutes vs 19 ± 13 minutes; P=.41) (Table 1).
Imaging analysis.
Comparison of LV function and volume between 3-5 day and 90-day imaging follow-up time points. By CMR imaging, LVEF improved significantly in patients with smaller IS (group 1) between 3-5 days and 30 days post PCI (from 49.2% to 55.1%; P<.001). No recovery was observed in patients with larger IS (group 2) (from 35.2% to 35.6%; P=.78) (Figure 2).
By echocardiography, LVEDV index (LVEDVi) size was unchanged in group 1 between 3-5 days and 90 days. LVEDVi size increased in patients with larger IS (group 2) between 3-5 day and 90-day follow-up (59.9 ± 16.8 mL/m2 vs 73.4 ± 14.2 mL/m2; P=.02) (Table 2). Group 1’s LVESV index (LVESVi) dimensions remained similar between the time points of 3-5 day and 90-day imaging follow-up (from 30.8 mL/m2 to 27.4 mL/m2; P=.17). Group 2 trended toward increased LVESVi dimensions between the time points of 3-5 day and 90-day imaging follow-up (from 37.2 ± 11.2 mL/m2 to 45.6 ± 14.4 mL/m2; P=.07).
Comparison of LV volume analysis by infarct size grouping (group 1 IS ≤25% vs group 2 >25%). At 3-5 day imaging follow-up, group 1 and group 2 had comparable LVEDVi (Table 3). At 90-day follow-up imaging, group 1 trended toward a smaller LVEDVi as compared with group 2 (62.0 ± 19.8 mL/m2 vs 72.5 ± 13.8 mL/m2; P=.07) (Table 3). LVESVi was not different between group 1 and group 2 at 3-5 day imaging follow-up. At 90-day imaging follow-up, group 1’s LVESVi was significantly smaller than group 2’s LVESVi (27.0 ± 12.9 mL/m2 vs 44.7 ± 14.1 mL/m2; P=.002) (Table 3).
Comparison of LV wall motion and function by infarct size grouping (group 1 IS ≤25% vs group 2 >25%). Group 1 had less hypokinesis/akinesis at 3-5 days and marked improvement in these parameters at 90 days (Figure 3). Group 2 had more extensive wall-motion abnormalities at 3-5 days and no improvement at 90 days.
Infarct size as a percentage of LV mass by CMR at 3-5 days was predictive of 30-day IS (R2=95.4%; Spearman’s ρ=0.983; P<.001) (Figure 4). Thirty-day CMR-derived LVEF was additionally predictive of 90-day echo-derived LVEF (R2=69.18; Spearman’s ρ=0.836; P<.001). Additionally, LVEF at 3-5 and 30-day follow-up by CMR demonstrated correlation to IS (Pearson correlation: -0.696 at 3-5 day CMR; Pearson correlation: -0.802 at 30-day CMR), with similar findings by 3-5 day and 90-day echo LVEF to IS (Pearson correlation: -0.651 at 3-5 day echo; Pearson correlation: -0.766 at 90-day echo) (Figure 5).
Subgroup analysis of patients with ΣSTE>6. Of the patients in group 1 and group 2 who had STE >6, a subgroup analysis was performed comparing their CMR findings at 3-5 day imaging follow-up vs 30-day imaging follow-up. In this subgroup, patients with smaller IS (group 1) had significantly greater LVEF at 3-5 day imaging follow-up, with sustained findings at 30-day imaging follow-up (P<.001) (Table 4). LVEDV dimensions trended toward increased size in group 2 vs group 1 at 3-5 day imaging without statistical significance (P=.07) (Table 4). On 30-day CMR follow-up, differences in LVEDV between group 1 and group 2 reached statistical significance; LVEDV was significantly larger in group 2 patients as compared with group 1 patients (P=.004). Of note, LVESV was additionally found to be significantly larger in group 2 as compared with group 1 at both 3-5 day (P=.001) and 30-day CMR imaging follow-up (P<.001).
Discussion
This feasibility study suggests amongst patients presenting with anterior STEMI: (1) delayed reperfusion following 30 minutes of Impella unloading improved LVEF when IS was ≤25% (group 1), while no improvement was noted for patients with IS >25% (group 2); (2) LVEDVi and LVESVi did not change in patients with IS ≤25% (group 1), but worsened among patients with IS >25% (group 2); and (3) there was a correlation between 3-5 day CMR measures of IS and 90-day echocardiography LVEF. These data suggest that reducing IS to ≤25% may reduce adverse remodeling. Furthermore, patients with 30 minutes of unloading prior to reperfusion exhibited a trend toward having a lower likelihood of developing IS >25%. Lastly, although group 1 had a longer time to reperfusion and longer time between symptom to reperfusion, neither variable resulted in a larger IS.
The Impella CP provides mechanical circulatory support and has been shown to decrease ventricular wall stress and increase forward flow, similar to other pneumatic and percutaneously delivered microaxial flow catheters.19-21 Despite the promising therapeutic potential of the Impella CP and other LV-unloading devices, a major concern to greater implementation is the fear that delayed door-to-balloon time may increase myocardial IS.22-25
Extent of IS is strongly correlated to long-term incidence of HF and mortality.26 The DTU-STEMI pilot trial has demonstrated the safety and feasibility of delaying reperfusion while unloading the LV during anterior STEMI intervention. Proof of efficacy and long-term clinical impact of this therapy requires a large, prospective, randomized trial, which is currently underway (NCT03947619). In this current study, measures of IS were obtained at early and later time points, with analogous echo-derived indices of myocardial size and contractibility at 3-5 day and 90-day imaging follow-up. This dataset provides a unique opportunity to correlate early measures of IS with late functional recovery and delayed adverse ventricular remodeling.
As highlighted recently by Heusch et al, the gold standard of cardioprotection is a reduction in IS.27 Numerous attempts to limit IS in experimental studies have been tested, yet the translation of cardioprotective approaches has been discouraging, with ambivalent results from clinical studies.22,28-32 Infarct size measured within 1 month after primary PCI for STEMI is a strong independent predictor of hospitalization for HF. There is a clear graded response between IS and the composite of mortality or hospitalization for HF, with every 5% increase in IS contributing to a 20% increase in the relative hazard ratio. Thus, attempts to therapeutically reduce IS may translate to less adverse LV remodeling with lower incidences of HF.33-35
In this analysis, patients from the DTU-STEMI trial with 3-5 day and 30-day CMR, and 90-day echo data available for analysis demonstrate that early 3-5 day CMR measurements of IS may be engaged as an early prognostic modality to identify patients who will have LV remodeling and also identifies a potential therapeutic goal for strategies focused on IS reduction. Specifically, 3-5 day CMR may be sufficient to capture the future direction of remodeling.
On post hoc analysis, patients were separated into 2 groups based off of IS (group 1 IS ≤25% and group 2 IS >25%). Numerically, group 1 contained a higher percentage of patients from the U-DR (unloading followed by delayed reperfusion) arm than group 2 (59% vs 33%, respectively; P=.18). While LVEF improved in group 1 between 3-5 day and either 30-day or 90-day follow-up, it was unchanged in group 2 (Figure 2). In addition, LVEDVi and LVESVi—indices of remodeling—worsened in group 2 (Table 2 and Table 3) and the proportion of patients with wall-motion abnormalities in the basal, mid-cavity, and apical regions at 90 days post PCI was higher (Figure 3).
A novel observation from matching CMR-derived IS with echo-derived IS measurements is that patients with larger IS presented with extensive akinesis of the anterior wall and adverse LV remodeling that did not improve over time. When assessing the total patient population, there was a negative correlation between 90-day echo-derived LVEF and IS at both 3-5 days and 30 days post therapy (data not shown). Group 1 had a higher percentage of patients with unloading followed by delayed reperfusion as compared with group 2, and a greater proportion of patients that were found to experience increased function and less adverse remodeling. These early findings are fundamental to the development of the larger DTU-STEMI pivotal trial comparing LV unloading and delayed reperfusion with current STEMI standard of care.
In addition to IS, coronary microvascular obstruction has been demonstrated to be predictive of 1-year hospitalization and mortality rates.36 In their study of 122 patients with STEMI and PCI with and without ischemic postconditioning therapy, Traverse et al found that IS in patients with postconditioning therapy was unchanged, but the extent of coronary microvascular obstruction was reduced.37 LVEDV and LVESV were also significantly smaller in patients with ischemic postconditioning. In the DTU-STEMI pilot study, there was a similar trend toward reduced microvascular obstruction on CMR in the delayed reperfusion arm, suggesting that mechanically unloading the LV before PCI may benefit the microvasculature in addition to reducing IS.14
Study limitations. This pilot study is limited by the small sample size, the lack of stratification based on IS, and the lack of a standard-of-care arm. Although this was a closely monitored trial, we were only able to obtain CMR measurements in 80% of patients. Furthermore, many patients were excluded from enrollment in the DTU pilot because of known contraindications to CMR imaging (permanent pacemakers, claustrophobia, impaired renal function, etc). Given the small number of patients in this post hoc analysis, all study results should be interpreted as hypothesis generating. The results from the pilot study support the safety and feasibility of mechanical unloading with delayed reperfusion, which is now being evaluated in a large-scale randomized, controlled trial against a standard-of-care arm, which also includes a longer period of follow-up for definitive clinical and imaging endpoints. If proven in the larger pivotal trial, timing of reperfusion with correlative early implementation of CMR imaging confirmation with a goal of reduction of IS to <25% of LV mass may become a new benchmark for trials attempting to reduce myocardial infarction size.
Conclusion
The early clinical prognostication value of CMR changes among patients randomized to immediate vs delayed reperfusion with mechanical remodeling is not well studied. Specifically, 3-5 day CMR measurements of IS may be an early prognostic modality to identify patients who will have LV remodeling and also identify a potential therapeutic marker for unloading strategies focused on IS reduction. These data demonstrate the feasibility of unloading during STEMI and indicate a potential target reduction in IS to improve post-therapy LV function. The findings are currently being tested in a larger randomized, controlled trial with potential implications on management and prognosis of patients. These findings highlight the need to further evaluate the application of mechanical unloading using the Impella CP and delayed reperfusion to activate a cardioprotective paradigm.
Acknowledgments. JetPub Scientific Communications LLC, supported by Abiomed, Inc, assisted in the preparation of this manuscript, in accordance with Good Publication Practice (GPP3) guidelines.
Affiliations and Disclosures
From 1Henry Ford Hospital, Detroit, Michigan; 2Abiomed, Inc, Danvers, Massachusetts; 3Columbia University, New York, New York; 4St Francis Heart Center, Roslyn, New York; 5Massachusetts Institute of Technology, Cambridge, Massachusetts; 6Wayne State University School of Medicine, Detroit, Michigan; 7Duke University, Durham, North Carolina; 8Yale University, New Haven, Connecticut; and 9Tufts Medical Center, Cardiovascular Center for Research and Innovation, Boston, Massachusetts.
Funding: Funding for this study was provided by Abiomed, Inc (Danvers, Massachusetts).
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kapur reports consulting/speaker honoraria and institutional grant support from Abbott Laboratories, Abiomed, Boston Scientific, Medtronic, LivaNova, MDStart, and Precardia. Dr O’Neill reports research funding and speaker/consulting honoraria from Abiomed. Dr Moses reports speaker/consulting honoraria from Abiomed. Dr Wang is a consultant for Edwards LifeSciences, Boston Scientific, Neochord, and Abbott. Dr Polak and Dr Josephy are employees of Abiomed. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript accepted May 4, 2022.
Address for correspondence: Dee Dee Wang, MD, Henry Ford Hospital, 2799 West Grand Blvd, CFP 439, Detroit, MI 48202. Email: dwang2@hfhs.org
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