Highlights
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Severe CAC is common in HRPCI and associated with more complex anatomy and comorbidities.
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Untreated severe CAC independently predicts 1-year mortality (HR: 1.71).
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Atherectomy appeared to be safe in Impella-supported HRPCI.
Severe coronary artery calcification (CAC) complicates high-risk percutaneous coronary intervention (HRPCI), particularly in patients with impaired left ventricular function. Atherectomy may facilitate lesion preparation, but its use in high-risk settings is limited. We therefore aimed to assess the impact of CAC severity and atherectomy on outcomes in Impella-supported HRPCI. In the PROTECT III study (NCT04136392), 1,015 of 1,237 patients had data on CAC severity and atherectomy. Patients were grouped as severe CAC without atherectomy ( n = 298), severe CAC with atherectomy ( n = 326), and no severe CAC ( n = 400). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE: all-cause death, myocardial infarction, stroke/TIA, or repeat revascularization) at 30- and 90-days. Secondary endpoints included 1-year mortality, PCI-related complications, and hemodynamic instability. Patients with severe CAC had higher baseline SYNTAX scores and more left main disease. Atherectomy was associated with slightly longer procedural times, but not increased periprocedural complications or hemodynamic instability. At 90 days, MACCE was highest in the untreated severe CAC group (16.1% vs 12.6% vs 9.2%; overall log-rank p = 0.048). One-year mortality was also highest in this group (23.7%; p = 0.02). However, CAC severity and atherectomy use were not independent predictors of outcomes. Sensitivity analysis excluding patients with atherectomy but no severe CAC showed higher mortality risk in untreated severe CAC cases (adjHR: 0.59; overall p = 0.026). In conclusion, Severe CAC is common in patients undergoing Impella-supported HRPCI and is associated with worse outcomes. Atherectomy was safe but its benefit remains uncertain. These findings highlight the prognostic relevance of CAC and the potential role of calcium modification in HRPCI.
Graphical Abstract
MACCE is defined as the composite of all-cause death, myocardial infarction, repeat revascularization, and stroke/transient ischemic attack. CKD = chronic kidney disease; LM = left main; LVEF = left ventricular ejection fraction; MACCE = major adverse cardiovascular and cerebrovascular events.
Introduction
Coronary artery calcification (CAC) is increasingly frequent in catheterization laboratories, with about 1/3 of lesions treated by percutaneous coronary intervention (PCI) presenting with significant angiographically-measured calcification. ,, This trend reflects aging populations, a higher burden of comorbidities such as diabetes and chronic kidney disease, and later presentation of advanced coronary artery disease (CAD). , Despite advances in technology, PCI of severely calcified lesions remains challenging due to impaired stent delivery, expansion, and apposition, which are key factors for procedural success and favorable clinical outcomes. ,,,,, Moderate to severe target lesion calcification is associated with increased risks of death, myocardial infarction (MI), stent thrombosis, and need for repeat revascularization. ,,,, Atherectomy is an effective calcium modification tool, but carries potential procedural risks, including vessel dissection, perforation, slow flow, and no-reflow phenomena. ,, These complications are particularly concerning in patients with low left ventricular ejection fraction (LVEF) and those undergoing high-risk PCI (HRPCI), given limited myocardial reserve and often compromised hemodynamics. This patient population has been largely excluded from major atherectomy trials. ,, This study addresses this gap by evaluating the effect of calcification and use of atherectomy in patients undergoing Impella-supported HRPCI.
Methods
Study design, population, and oversight
The PROTECT III, a substudy of the global cVAD registry (NCT04136392), study design, rationale, and initial results have been previously published. To summarize, the PROTECT III study is a Food and Drug Administration (FDA)-audited postapproval, observational study on patients undergoing elective or urgent HRPCI procedures, excluding those with cardiogenic shock. Patients were enrolled between March 2017 and March 2020 across 46 centers in North America to assess percutaneous left ventricular assist device (pLVAD) support in patients undergoing elective or urgent HPRCI procedures. Impella 2.5 or Impella CP was used for hemodynamic support during the procedures, with the decision to utilize Impella and define HRPCI left to the discretion of the treating physician, based on their standard of care. Patients were eligible for enrollment once the decision to use Impella was made either prior to or during the index PCI. Cases involving bailout pLVAD implantation were excluded, and patients undergoing cardiogenic shock were excluded. Patients with available echocardiographic core laboratory assessment, calcification severity assessment, and adjunct therapy diagnostics were included for assessment.
The study was approved by the applicable Institutional Review Board or Independent Ethics Committee at each participating site prior to enrollment and was conducted in accordance with the Declaration of Helsinki. Baseline patient demographics, blood tests, echocardiography were collected before index procedure and patients were followed for 90 days. Angiographic data analysis was performed by an independent core lab (Beth Israel Deaconess Medical Center Angiographic Core Laboratory, Boston, MA, USA). A 12-member independent steering committee oversaw the cVAD study’s conduct, while an independent Clinical Events Committee adjudicated major adverse cardiovascular and cerebrovascular events (MACCE), as well as their relationship to the procedure and/or device. The sponsor, Abiomed Inc. (Danvers, MA, USA), managed study data, performed source document verification, and funded the Cardiovascular Research Foundation (New York, NY) for statistical analysis. The authors had unrestricted access to the study data and accept full responsibility for the integrity of this report.
Definitions and end points
Severe calcification was assessed angiographically by an independent core laboratory, and was defined as radiopacities visible without cardiac motion, prior to contrast injection, and involving both sides on arterial lumen.
The primary endpoint was MACCE, defined as the composite of all-cause mortality, MI, stroke/transient ischemic attack, and repeat revascularization at 30 and 90 days. Secondary endpoints included: (1) 1-year all-cause mortality; (2) PCI-related complications, including coronary dissection, perforation, acute closure, no-reflow, side branch compromise, stent thrombosis, arrhythmia, and cardiac arrest; (3) hypotension during support, defined as a systolic blood pressure below 90 mmHg lasting more than 5 minutes, requiring administration of inotropic or vasopressor medications or intravenous fluids while the patient was supported with a hemodynamic support device; and (4) duration of PCI. Detailed definitions of PCI-related complications have been previously published (17).
Statistical analyses
Baseline characteristics are summarized with mean ± standard deviation or median and interquartile range (IQR) for continuous measures and proportions for categorical variables. Comparison between the study groups for categorical variables are summarized as percentages and were analyzed using the Chi-square or Fisher’s exact test (e.g., PCI complications), where continuous variables (e.g., age) are summarized as mean ± standard deviation and median [IQR] and compared using analysis of variance (ANOVA) and Wilcoxon Rank-Sum test. For time-to-first event analyses, event rates are estimated by the Kaplan–Meier method and compared with the log-rank test. Multivariable Cox proportional hazards model is applied to compare patient groups and their association with 90-day MACCE and 1-year all-cause mortality after adjustment for age, sex, estimated glomerular filtration rate (eGFR), LVEF, anemia, PCI status, left main disease, and bifurcation lesions. An additional sensitivity analysis, excluding atherectomy patients in no-severe calcification group, was performed for the 90-day MACCE and 1-year mortality using log-rank test and multivarivable Cox prorpotional hazards model. Multiple imputations using Fully Conditional Specification (FCS) method were used to account for missing data for covariates used in the multivariable Cox proportional hazards models. All p values are 2-tailed, and p <0.05 was considered significant for all analyses. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).
Data transparency and openness
Due to the sensitive nature of the data collected in this study, qualified researchers with appropriate training in human subject confidentiality protocols may request access to the dataset by contacting the study sponsor, Abiomed, at aalmedh1@its.jnj.com.
Results
Baseline demographics and procedural characteristics
The PROTECT III study enrolled 1,237 consecutive patients across 46 sites in North America between March 2017 and March 2020. Of these, 1,015 patients had core laboratory data available on calcification severity and the use of adjunctive atherectomy therapy ( Figure 1 ). At baseline, 29% (298 patients) had severe calcification without atherectomy, 32% (326 patients) had severe calcification with atherectomy, and 39% (400 patients) did not have severe calcification. Compared to patients without severe calcification, those with severe calcification were generally older and exhibited more diffuse CAD, reflected by higher preprocedural SYNTAX scores (30.5 in severe calcification without atherectomy, 31.5 in severe calcification with atherectomy, vs 23.2 in no severe calcification, overall p-value <0.0001) and a higher prevalence of left main artery disease (59% for severe calcification without atherectomy, 66% with severe calcification and atherectomy, versus 50% in no severe calcification, overall p-value <0.0001). Intravascular imaging was more frequently used in patients with calcification who had atherectomy compared to patients with calcification without atherectomy or patients with no calcification (55% vs 44% and 41% respectively, p-value = 0.0008).
Study flow chart.
Compared to patients with severe calcification, patients without severe calcification had higher rates of peripheral vascular disease, a history of prior PCI or CABG, and lower LVEF. Despite the higher preprocedural SYNTAX scores in the severe calcification groups, there were no significant differences in postprocedural SYNTAX scores among the groups ( Table 1 ).
Table 1
Baseline patient demographics and procedural characteristics
| Severe calcification without atherectomy | Severe calcification with atherectomy | No severe calcification |
Overall
p-value |
|
|---|---|---|---|---|
| ( n = 289) | ( n = 326) | ( n = 400) | ||
| Demographics | ||||
| Age, year |
71.1 ± 9.8
n = 289 |
75.0 ± 9.5
n = 326 |
68.0 ± 11.9
n = 400 |
<0.0001 |
| Sex, male | 219 (75.8%) | 234 (71.8%) | 293 (73.5%) | 0.53 |
| Race | ||||
| White or Caucasian | 194 (67.1%) | 215 (66.0%) | 251 (62.8%) | 0.45 |
| Black or African American | 36 (12.5%) | 32 (9.8%) | 69 (17.3%) | 0.01 |
| Asian | 11 (3.8%) | 14 (4.3%) | 8 (2.0%) | 0.18 |
| American Indian or Alaska native | 0 (0%) | 1 (0.3%) | 2 (0.5%) | 0.49 |
| Native Hawaiian/Other Pacific Islander | 1 (0.3%) | 0 (0%) | 0 (0%) | 0.28 |
| Other race | 10 (3.5%) | 6 (1.8%) | 17 (4.3%) | 0.19 |
| Body Mass Index, kg/m 2 |
28.0 ± 5.5
n = 286 |
28.2 ± 6.4
n = 325 |
29.7 ± 7.3
n = 399 |
0.0008 |
| Medical history | ||||
| History of tobacco use | 176 (63.1%) | 202 (63.9%) | 238 (60.6%) | 0.63 |
| Hypertension | 260 (90.0%) | 298 (92.5%) | 358 (90.2%) | 0.45 |
| Dyslipidemia | 224 (78.0%) | 265 (82.0%) | 305 (76.8%) | 0.22 |
| Diabetes | 162 (56.1%) | 178 (54.9%) | 219 (55.2%) | 0.96 |
| Peripheral vascular disease | 60 (21.0%) | 106 (23.2%) | 64 (32.7%) | 0.047 |
| Anemia | 45 (17.6%) | 72 (25.9%) | 54 (15.4%) | 0.003 |
| Chronic Pulmonary Disease | 61 (21.3%) | 83 (25.7%) | 85 (21.6%) | 0.33 |
| Stroke/TIA | 44 (15.3%) | 64 (19.8%) | 62 (15.7%) | 0.24 |
| Renal insufficiency | 90 (31.1%) | 116 (36.0%) | 104 (26.3%) | 0.02 |
| eGFR, mL/min/1.73 m 2 |
68.6 ± 24.9
n = 227 |
65.7 ± 23.3
n = 251 |
69.9 ± 24.4
n = 312 |
0.12 |
| Prior myocardial infarction | 111 (40.5%) | 118 118 (37.1%) | 162 (42.0%) | 0.41 |
| Prior PCI | 113 (39.6%) | 105 (32.6%) | 163 (41.0%) | 0.056 |
| Prior coronary artery bypass grafting | 39 (13.6%) | 34 (10.5%) | 67 (16.8%) | 0.047 |
| Heart failure | 176 (61.3%) | 192 (59.4%) | 229 (57.8%) | 0.66 |
| Left ventricular ejection fraction, % |
32.0 ± 13.9
n = 228 |
37.4 ± 15.4
n = 253 |
34.2 ± 16.0
n = 309 |
0.0005 |
| Atrial fibrillation | 12 (41.4%) | 15 (38.5%) | 11 (31.4%) | 0.69 |
| Indication for PCI | ||||
| Acute coronary syndrome | 157 (61.3%) | 157 (55.7%) | 199 (55.7%) | 0.31 |
| Urgent PCI | 146 (50.5%) | 180 (55.2%) | 197 (49.3%) | 0.26 |
| Number of diseased vessels | ||||
| 1 | 24 (8.4%) | 24 (7.4%) | 58 (14.6%) | 0.003 |
| 2 | 91 (31.8%) | 86 (26.5%) | 137 (34.5%) | 0.07 |
| 3 | 165 (57.7%) | 207 (63.9%) | 198 (49.9%) | 0.0007 |
| Left main disease | 170 (58.8%) | 214 (66.3%) | 196 (49.5%) | <0.0001 |
| Number of vessels treated | ||||
| 1 | 71 (26.6%) | 83 (28.3%) | 121 (32.7%) | 0.21 |
| 2 | 114 (42.7%) | 134 (45.7%) | 167 (45.1%) | 0.75 |
| 3 | 82 (30.7%) | 76 (25.9%) | 82 (22.2%) | 0.052 |
| Intravascular imaging (IVUS/OCT) | 126 (43.6%) | 178 (54.6%) | 161 (41.1%) | 0.0008 |
| Pre-PCI SYNTAX score |
30.5 ± 12.9
n = 242 |
31.5 ± 12.3
n = 266 |
23.2 ± 10.7
n = 322 |
<0.0001 |
| Post-PCI SYNTAX score |
6.9 ± 8.8
n = 240 |
7.1 ± 8.3
n = 264 |
6.1 ± 8.0
n = 317 |
0.27 |
| Pre-PCI Ischemia Jeopardy score |
9.1 ± 1.9
n = 275 |
9.3 ± 1.9
n = 307 |
8.3 ± 2.3
n = 371 |
<0.0001 |
| Post-PCI Ischemia Jeopardy score |
2.0 ± 2.1
n = 273 |
2.1 ± 2.1
n = 305 |
1.8 ± 2.1
n = 366 |
0.11 |
Data are presented as mean ± standard deviation (n) or n (%).
EGFR = estimated glomerular filtration rate; IVUS = intravascular imaging; OCT = optical coherence tomography; PCI = percutaneous coronary intervention; SYNTAX = synergy between percutaneous coronary intervention with taxus and cardiac surgery; TIA = transient ischemic attack.
Admission and procedural adverse events
Duration of PCI was significantly longer in the atherectomy group, with a mean duration of 2.3 ± 1.1 hours (median 2.2 [1.6, 2.9] hours), compared to 2.0 ± 1.1 hours (median 1.8 [1.2, 2.6] hours) in the severe calcification without atherectomy group, and 1.8 ± 0.9 hours (median 1.7 [1.1, 2.3] hours) in the no severe calcification group (p <0.0001) ( Table 2 ). PCI-related complications occurred in 5% of patients with severe calcification without atherectomy (14/264), 7% in those with severe calcification with atherectomy (19/284), and 3% in the no severe calcification group (12/353). The overall complication rate across all groups was 5% (45/901), with no statistically significant difference between groups (p = 0.16). Hypotension requiring vasopressor or fluid administration during Impella support occurred in 4% (11/289) of patients with severe calcification without atherectomy, 5% (16/326) in those with severe calcification with atherectomy, and 3% (13/399) in the no severe calcification group. The overall incidence was 4% (40/1,014), with no statistically significant difference between groups (p = 0.52).
Table 2
Procedural complications and in-hospital adverse events
|
Severe calcification without atherectomy
( N = 289) |
Severe calcification with atherectomy
( N = 326) |
No severe calcification
( N = 400) |
Overall
p-value |
|
|---|---|---|---|---|
| Duration of hospitalization (days, presented as median [IQR]) | 6.0 [3.0, 10.0] n = 285 | 6.0 [2.0, 11.0] n = 321 | 6.0 [2.0, 10.0] n = 399 | 0.19 |
| Hypotension during support | 11/289 (3.8%) | 16/326 (4.9%) | 13/399 (3.3%) | 0.52 |
| PCI-related complications * | 14/264 (5.3%) | 19/284 (6.7%) | 12/353 (3.4%) | 0.16 |
| No Reflow | 1/14 (7.1%) | 0/19 (0%) | 0/12 (0%) | 0.32 |
| Abrupt Closure | 1/14 (7.1%) | 0/19 (0%) | 1/12 (8.3%) | 0.46 |
| Dissection | 3/14 (21.4%) | 4/9 (21.1%) | 1/12 (8.3%) | 0.61 |
| Distal Embolization | 0/14 (0%) | 0/19 (0%) | 1/12 (8.3%) | 0.25 |
| Perforation | 5/14 (35.7%) | 5/19 (26.3%) | 6/12 (50%) | 0.61 |
| Failure Stent Deployment | 3/14 (21.4%) | 2/19 (10.5%) | 0/12 (0%) | 0.22 |
| Arrhythmia | 2/14 (14.3%) | 1/19 (5.3%) | 0/12 (0%) | 0.33 |
| Adverse events | ||||
| Pericardial effusion requiring pericardiocentesis | 2/289 (0.7%) | 5/326 (1.5%) | 6/399 (1.5%) | 0.57 |
| Cardiac arrest | 9/289 (3.1%) | 9/326 (2.8%) | 6/399 (1.5%) | 0.33 |
| Cardiogenic shock | 6/289 (2.1%) | 10/326 (3.1%) | 5/399 (1.3%) | 0.23 |
| Ventricular arrhythmia | 8/289 (2.8%) | 5/326 (1.5%) | 5/399 (1.3%) | 0.31 |
| AKI (Stage 2 or 3) | 14/289 (4.8%) | 15/326 (4.6%) | 15/399 (3.8%) | 0.76 |
| Life-threatening/disabling/major bleeding (BARC ≥3a) | 6/289 (2.1%) | 7/326 (2.1%) | 13/399 (3.3%) | 0.53 |
| Hemolysis | 3/289 (1.0%) | 4/326 (1.2%) | 7/399 (1.8%) | 0.70 |
| Thrombocytopenia | 3/289 (1.0%) | 4/326 (1.2%) | 2/399 (0.5%) | 0.55 |
| Complete heart block | 1/289 (0.3%) | 5/326 (1.5%) | 3/399 (0.8%) | 0.27 |
|
Vascular/cardiac structural complication requiring
surgery/re-intervention |
2/289 (0.7%) | 2/326 (0.6%) | 2/399 (0.5%) | 0.95 |
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