2021 Volume 85 Issue 1 Pages 50-58
Background: Moderate/severe coronary artery calcification (CAC) predicts worse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). However, to date most studies have been modest in size and with limited follow-up. We aimed to assess the association between calcification severity and long-term clinical outcomes in a large cohort undergoing PCI.
Methods and Results: In total, 10,068 consecutive patients who underwent PCI at Fuwai Hospital were enrolled in this prospective observational study. Patients were categorized as none/mild or moderate/severe CAC according to the severity of the target lesion by visual assessment of coronary angiography. Major adverse cardiovascular events (MACE), a composite event of death, myocardial infarction and revascularization, at 5 years were assessed. None/mild CAC was observed in 8,229 (81.7%) patients, and moderate/severe CAC was observed in 1,839 (18.3%) patients. Patients with moderate/severe CAC had a significantly higher rate of 5-year unplanned revascularization (15.2% vs. 13.2%, P=0.022) and MACE (20.7% vs. 17.9%, P=0.005). After propensity score matching, the moderate/severe CAC group still had a higher rate of 5-year unplanned revascularization (15.2% vs. 12.6%, P=0.019). Cox regression analysis using clinically significant variables revealed moderate/severe calcification was independently associated with higher risk of 2-year unplanned target vessel revascularization (hazard ratio (HR)=1.287, 95% confidence interval (CI): 1.036–1.600, P=0.023) and MACE (HR=1.242, 95% CI: 1.039–1.484, P=0.017), but not 5-year unplanned revascularization and MACE.
Conclusions: In patients undergoing PCI, moderate/severe coronary calcification increases the risk of long-term MACE.
Coronary artery calcification (CAC) occurs with the development of advanced atherosclerosis,1 and is associated with arterial stiffness, resulting in reduced vasomotor responses and impaired myocardial perfusion.2,3 In patients undergoing percutaneous coronary intervention (PCI), heavy CAC is associated with higher residual stenosis and smaller minimum stent area, and higher rates of stent under-expansion and malapposition4,5 and stent fracture,6 all of which increase the risk of adverse clinical outcomes.
Prior studies have investigated the prognostic effect of CAC on patients undergoing PCI. Sharma et al demonstrated that patients with severe CAC fared worse than patients with none/mild CAC in terms of 1-year major adverse cardiac events (MACEs), but comparable outcomes were observed between moderate CAC and none/mild CAC patients.7 Similarly, in a large-sample retrospective study, Copeland-Halperin et al found that patients with moderate or severe CAC had significantly higher risk of 1-year MACE following PCI with newer generation drug-eluting stents.8 Another observational study involving 7,429 patients undergoing PCI from the TAXUS Peri-Approval Registry: A Multi-Center Safety Surveillance (ARRIVE) registry reported that moderate/severe CAC was independently associated with higher risk of 2-year MACE and death.9 However, all those studies were limited by their modest sample size or short follow-up period. To the best of our knowledge, large-scale studies with long-term clinical outcomes in patients with CAC undergoing PCI are lacking, so we investigated the effect of CAC on 5-year MACE in a large cohort of patients undergoing PCI.
Between January 2013 and December 2013, data for a total of 10,724 consecutive patients undergoing PCI were prospectively collected from a high-volume center (Fu Wai Hospital, National Center for Cardiovascular Diseases, Beijing, China), without predefined inclusion criteria. Exclusion criteria included: patients with the target lesion within a bypass graft (n=60), or target lesion was in-stent restenosis (n=545). Patients lost to 2-year follow-up (n=51) were also excluded from analysis. Patients were subsequently categorized into moderate/severe calcification or none/mild calcification group according to the calcification severity of the target lesion. Severity of calcification was classified from visual assessment via coronary angiography by 2 experienced interventional cardiologists who were independent of this study: none/mild calcification, moderate calcification (radiopacities noted with cardiac motion before contrast injection), and severe calcification (radiopacities noted without cardiac motion before contrast injection)10,11 (Figure 1, Supplementary Movie). The study protocol was in accordance with the Declaration of Helsinki and the ethical standards of Fuwai Hospital. The institutional review board (Ethics Committee of Fuwai Hospital) approved the study protocol (IRB approval no. 2017-860). Enrolled patients gave written informed consent before the intervention.
Patient flowchart. CAC, coronary artery calcification; F/U, follow-up; PCI, percutaneous coronary intervention.
The PCI strategy, stent type, use of intracoronary imaging and rotational atherectomy were left to the interventionist’s discretion. Unless on chronic P2Y12 inhibitor therapy for >6 days, elective PCI patients received oral 300 mg aspirin and clopidogrel (loading dose 300 mg) or ticagrelor (loading dose 180 mg) at least 24 h before the procedure. Patients presenting as acute coronary syndrome (ACS) scheduled for PCI received the same dose of aspirin and ticagrelor or clopidogrel (loading dose 300 or 600 mg) as soon as possible. During the procedure, unfractionated heparin (100 U/kg) was administered to all patients, and the use of glycoprotein IIb/IIIa inhibitors was per the operator’s judgment. After the procedure, aspirin was prescribed at a dose of 100 mg daily indefinitely and clopidogrel 75 mg daily or ticagrelor 90 mg twice daily for at least 1 year after PCI.
Patient Follow-upBaseline characteristics, and the angiographic and PCI features were recorded during each patient’s hospitalization. All patients were evaluated by clinic visit or by telephone interview at 1, 6, and 12 months postoperatively and annually thereafter. Patients were advised to return for coronary angiography if clinically indicated by symptoms or documentation of myocardial ischemia.
EndpointsThe primary endpoint was major adverse cardiovascular event (MACE), defined as the occurrence of death, myocardial infarction (MI), or unplanned revascularization during follow-up. Secondary endpoints included all-cause death, cardiac death, MI, revascularization, stent thrombosis (ST), stroke and bleeding. Death that could not be attributed to a noncardiac etiology was considered as cardiac death. MI was defined by the 3rd universal definition.12 Revascularization was defined as repeat revascularization for ischemic symptoms and events driven by PCI or surgery of any vessel. ST was defined according to the Academic Research Consortium, including definite, probable and possible in the analysis.13 Bleeding was quantified according to the Bleeding Academic Research Consortium Definition (BARC) criteria, including types 2, 3 and 5 in the analysis.14 Major bleeding was defined as types 3 and 5 from the BARC criteria. All endpoints were adjudicated centrally by 2 independent cardiologists.
Statistical AnalysisContinuous variables are expressed as mean±standard deviation or median with interquartile range, and categorical variables are presented as percentages. Differences in baseline characteristics and clinical outcomes between groups were assessed using the chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or the Wilcoxon rank test for continuous variables, as appropriate. Survival curves were constructed using the Kaplan-Meier method, and log-rank test was performed to compare time to clinical endpoints. Landmark survival analysis was performed for MACE and unplanned revascularization, with 30-day, 1-year and 2-year landmark time points. Cox regression analyses were conducted to evaluate the adjusted effect of moderate/severe CAC on clinical endpoints using 2 different multivariable models. Clinically and statistically significant covariates were entered into model 1, including age, sex, current smoker, diabetes, history of MI, history of coronary artery bypass grafting (CABG), and renal failure. In addition to the covariates included in model 1, model 2 included procedure-related variables such as the number of diseased vessels, pre-/postprocedural TIMI flow grade, and no-reflow/slow reflow phenomenon. Results were reported as adjusted hazard ratios (HRs) together with corresponding 95% confidence intervals (CI). Post-hoc subgroup analysis was performed to investigate whether significant interactions existed between CAC severity and clinical subgroups, including age, sex, smoking status, history of CABG, diabetes, SYNTAX score, baseline estimated glomerular filtration rate (eGFR), and ACS presentation. To minimize the effect of confounding factors caused by differences in baseline characteristics between the moderate/severe CAC and none/mild CAC groups, propensity score matching was performed. A propensity score was estimated for each patient using a logistic regression model. Patients were matched on estimated propensity scores, using the nearest neighbor approach. The matched variables were age, sex, current smoker, diabetes, history of MI, history of CABG, and renal failure. For all analyses, a 2-sided P value <0.05 was considered significant. Statistical analysis was performed using IBM® SPSS® v22.0.0.0 software (SPSS Inc., Chicago, IL, USA).
Among the 10,068 patients enrolled, 1,839 (18.3%) patients satisfied the criteria for the moderate/severe CAC group, and 8,229 (81.7%) belonged to the none/mild CAC group (Figure 1). Compared with patients with none/mild CAC, patients with moderate/severe CAC had worse general baseline conditions, including higher age, higher proportion of diabetes, hypertension, history of CABG, history of stroke, and renal failure (all P<0.05) (Table 1). Logistic multivariate analysis revealed that higher age (odds ratio (OR)=1.015, 95% CI: 1.007–1.022), history of CABG (OR=1.540, 95% CI: 1.135–2.089) and hypertension (OR=1.174, 95% CI=1.021–1.351) were independent predictors of moderate/severe CAC (Table 2).
| Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|
| None/mild calcification (n=8,229) |
Moderate/severe calcification (n=1,839) |
P value | None/mild calcification (n=1,839) |
Moderate/severe calcification (n=1,839) |
P value | |
| Age (years) | 57.85±10.21 | 60.01±10.62 | <0.001# | 60.20±10.44 | 60.01±10.62 | 0.592 |
| Male, n (%) | 6,355 (77.23) | 1,373 (74.66) | 0.018# | 1,375 (74.77) | 1,373 (74.66) | 0.940 |
| Body mass index, kg/m2 | 25.95±3.18 | 25.86±3.25 | 0.270 | 25.83±3.26 | 25.86±3.25 | 0.832 |
| Risk factors and history, n (%) | ||||||
| Smoker | 4,703 (57.15) | 1,021 (55.52) | 0.201 | 1,017 (55.30) | 1,021 (55.52) | 0.894 |
| Diabetes | 2,389 (29.03) | 626 (34.04) | <0.001# | 629 (34.20) | 626 (34.04) | 0.917 |
| On insulin | 820 (34.32) | 210 (33.55) | 0.715 | 219 (34.82) | 210 (33.55) | 0.635 |
| Hypertension | 5,235 (63.62) | 1,252 (68.08) | <0.001# | 1,179 (64.11) | 1,252 (68.08) | 0.011# |
| Hyperlipidemia | 5,496 (66.79) | 1,240 (67.43) | 0.598 | 1,219 (66.29) | 1,240 (67.43) | 0.462 |
| Peripheral artery disease | 206 (2.50) | 56 (3.05) | 0.187 | 69 (3.75) | 56 (3.05) | 0.237 |
| Prior MI | 1,453 (17.66) | 345 (18.76) | 0.264 | 335 (18.22) | 345 (18.76) | 0.671 |
| History of PCI | 1,709 (20.77) | 396 (21.53) | 0.466 | 373 (20.28) | 396 (21.53) | 0.351 |
| History of CABG | 267 (3.24) | 85 (4.62) | 0.004# | 77 (4.18) | 85 (4.62) | 0.520 |
| Prior stroke | 858 (10.43) | 232 (12.62) | 0.006# | 210 (11.42) | 232 (12.62) | 0.265 |
| Renal failure* | 300 (3.65) | 114 (6.20) | <0.001# | 102 (5.55) | 114 (6.20) | 0.400 |
| ESRD | 0 (0) | 0 (0) | 1.000 | 0 (0) | 0 (0) | 1.000 |
| Laboratory tests | ||||||
| Leukocytes, ×109/L | 6.89±2.04 | 6.93±2.01 | 0.435 | 6.91±2.03 | 6.93±2.01 | 0.721 |
| Platelets, ×109/L | 205.57±54.66 | 207.01±55.02 | 0.307 | 202.53±54.08 | 207.01±55.02 | 0.013 |
| Hemoglobin, g/L | 143.24±15.32 | 141.38±15.93 | <0.001# | 141.83±15.43 | 141.38±15.93 | 0.380 |
| Creatinine clearance, mL/min | 91.82±14.85 | 89.37±16.24 | <0.001# | 76.07±16.63 | 89.37±16.24 | 0.669 |
| GFR, mL/min | 91.82±14.85 | 89.37±16.24 | <0.001# | 89.45±15.72 | 89.37±16.24 | 0.884 |
| LVEF, % | 62.91±7.25 | 62.41±7.62 | 0.012# | 62.61±7.49 | 62.41±7.62 | 0.416 |
| LVEF <40%, n (%) | 95 (1.18) | 24 (1.33) | 0.587 | 34 (1.9) | 24 (1.33) | 0.190 |
| hs-CRP | 1.63 (0.79, 3.72) | 1.67 (0.87, 3.84) | 0.156 | 1.76 (0.82, 4.13) | 1.67 (0.87, 3.84) | 0.600 |
| BNP, pmol/L | 584.95 (452.10, 807.95) |
605.55 (462.10, 840.15) |
0.015# | 611.30 (461.25, 846.85) |
605.55 (462.10, 840.15) |
0.931 |
| LDL-C, umol/L | 2.51±0.91 | 2.52±0.93 | 0.732 | 2.52±0.95 | 2.52±0.93 | 0.913 |
| Triglycerides | 1.53 (1.15, 2.10) | 1.53 (1.12, 2.08) | 0.635 | 1.52 (1.14, 2.05) | 1.53 (1.12, 2.08) | 0.594 |
| HbA1c | 6.58±1.22 | 6.73±1.32 | <0.001# | 6.66±1.25 | 6.73±1.32 | 0.139 |
| Clinical presentation, n (%) | ||||||
| STEMI | 1,135 (13.79) | 253 (13.76) | 0.968 | 246 (13.38) | 253 (13.76) | 0.400 |
| NSTEMI | 364 (4.42) | 88 (4.79) | 0.498 | 90 (4.89) | 88 (4.79) | 0.878 |
| UA | 3,509 (42.64) | 715 (38.88) | 0.003# | 817 (44.43) | 715 (38.88) | 0.001# |
| SA | 3,220 (39.13) | 783 (42.58) | 0.006# | 685 (37.25) | 783 (42.58) | 0.001# |
| Medications at discharge, n (%) | ||||||
| Aspirin | 8,130 (98.80) | 1,815 (98.69) | 0.719 | 1,823 (99.13) | 1,815 (98.69) | 0.203 |
| Clopidogrel | 8,212 (99.79) | 1,834 (99.73) | 0.790 | 1,834 (99.73) | 1,834 (99.73) | 1.000 |
| Ticagrelor | 15 (0.18) | 3 (0.16) | 1.000 | 4 (0.22) | 3 (0.16) | 1.000 |
| β-blocker | 7,410 (90.05) | 1,661 (90.32) | 0.723 | 1,637 (89.02) | 1,661 (90.32) | 0.194 |
| Calcium-channel blocker | 4,007 (48.69) | 886 (48.18) | 0.689 | 897 (48.78) | 886 (48.18) | 0.717 |
| Nitrates | 8,046 (97.78) | 1,792 (97.44) | 0.389 | 1,810 (98.42) | 1,792 (97.44) | 0.037# |
| Statins | 7,917 (96.21) | 1,752 (95.27) | 0.062 | 1,770 (96.25) | 1,752 (95.27) | 0.141 |
Values are mean±SD or n (%). *Defined as eGFR <60 mL/min/1.73 m2. #Indicate statistical significance. BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; ESRD, endstage renal disease; GFR, glomerular filtration rate; HbA1c, hemoglobin A1c; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PSM, propensity score matching; SA, stable angina; STEMI, ST-elevation myocardial infarction; UA, unstable angina.
| Predictor | OR | 95% CI | P value |
|---|---|---|---|
| Age | 1.015# | 1.007–1.022# | 0.000# |
| Sex, female vs. male | 1.084 | 0.891–1.319 | 0.420 |
| Current smoker | 0.967 | 0.830–1.127 | 0.669 |
| Diabetes | 1.125 | 0.943–1.342 | 0.189 |
| History of MI | 1.100 | 0.919–1.316 | 0.298 |
| History of CABG | 1.540# | 1.135–2.089# | 0.006# |
| Renal failure | 1.242 | 0.904–1.707 | 0.181 |
| LVEF | 0.996 | 0.986–1.006 | 0.432 |
| Hypertension | 1.174# | 1.021–1.351# | 0.024# |
| Peripheral artery disease | 1.098 | 0.744–1.621 | 0.638 |
| History of stroke | 1.101 | 0.897–1.352 | 0.359 |
| Hemoglobin | 0.998 | 0.993–1.003 | 0.454 |
| HbA1c | 1.031 | 0.964–1.102 | 0.374 |
| BNP | 1.000 | 1.000–1.000 | 0.848 |
| Triglyceride | 0.997 | 0.936–1.061 | 0.913 |
| UA | 0.959 | 0.769–1.195 | 0.707 |
| Stable angina | 1.168 | 0.936–1.457 | 0.170 |
| Statins | 0.990 | 0.703–1.394 | 0.954 |
#Indicate statistical significance. Abbreviations as in Table 1.
Patients with moderate/severe CAC also had significantly worse angiographic findings and underwent more complex PCI than those with none/mild CAC, characterized by higher SYNTAX score, lower PCI success rate, higher rate of total occlusion, worse angulation and tortuosity, and greater usage of rotablation, intravascular ultrasound (IVUS) and intra-aortic balloon pump (IABP), etc. (all P<0.05) (Table 3).
| Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|
| None/mild calcification (n=8,229) |
Moderate/severe calcification (n=1,839) |
P value | None/mild calcification (n=1,839) |
Moderate/severe calcification (n=1,839) |
P value | |
| No. of target lesions | 1.00 (1.00, 2.00) | 1.00 (1.00, 2.00) | <0.001# | 1.00 (1.00, 2.00) | 1.00 (1.00, 2.00) | <0.001# |
| No. of diseased vessels | ||||||
| 1 | 6,510 (79.11) | 1,213 (65.96) | <0.001# | 1,397 (75.97) | 1,213 (65.96) | <0.001# |
| 2 | 1,598 (19.42) | 538 (29.26) | <0.001# | 409 (22.24) | 538 (29.26) | <0.001# |
| 3 | 121 (1.47) | 88 (4.79) | <0.001# | 33 (1.8) | 88 (4.79) | <0.001# |
| SYNTAX score | ||||||
| Baseline | 10.00 (5.50, 16.00) |
12.50 (7.00, 19.50) |
<0.001# | 10.00 (5.00, 16.00) |
12.50 (7.00, 19.50) |
<0.001# |
| Residual | 0.00 (0.00, 6.00) | 3.00 (0.00, 8.50) | <0.001# | 0.00 (0.00, 6.00) | 3.00 (0.00, 8.50) | <0.001# |
| Successful PCI | 7,970 (96.85) | 1,689 (91.84) | <0.001# | 1,808 (98.31) | 1,689 (91.84) | <0.001# |
| B2 or C type lesion | 8,359 (70.39) | 1,802 (81.32) | <0.001# | 1,371 (74.6) | 1,802 (81.32) | <0.001# |
| Lesion length | 22.00 (15.00, 33.00) |
27.00 (18.00, 42.00) |
<0.001# | 25.00 (16.00, 38.00) |
27.00 (18.00, 42.00) |
<0.001# |
| Lesion minimal diameter | 0.35 (0.20, 0.60) | 0.30 (0.04, 0.54) | <0.001# | 0.40 (0.25, 0.60) | 0.30 (0.04, 0.54) | 0.101 |
| Diameter stenosis (%) | 90.00 (80.00, 95.00) |
90.00 (80.00, 99.00) |
<0.001# | 90.00 (80.00, 95.00) |
90.00 (80.00, 99.00) |
<0.001# |
| Total occlusion | 1,405 (11.83) | 435 (19.63) | <0.001# | 272 (14.80) | 435 (19.63) | <0.001# |
| Ostial lesion | 1,604 (13.51) | 380 (17.15) | <0.001# | 317 (17.24) | 380 (17.15) | <0.001# |
| Moderate/severe tortuosity* | 4,871 (41.85) | 1,625 (74.03) | <0.001# | 841 (46.41) | 1,625 (74.03) | <0.001# |
| Moderate/severe angulation** | 972 (8.36) | 298 (13.63) | <0.001# | 175 (9.7) | 298 (13.63) | <0.001# |
| Bifurcation lesion | 2,042 (17.20) | 409 (18.46) | 0.151 | 360 (19.58) | 409 (18.46) | 0.021# |
| Thrombotic lesion | 353 (3.10) | 62 (2.93) | 0.672 | 71 (3.99) | 62 (2.93) | 0.632 |
| Target vessel | ||||||
| LM | 436 (3.67) | 94 (4.24) | 0.195 | 98 (5.33) | 94 (4.24) | 0.083 |
| LAD | 4875 (41.05) | 994 (44.86) | 0.001# | 994 (54.05) | 994 (44.86) | <0.001# |
| LCX | 2,224 (18.73) | 341 (15.39) | <0.001# | 454 (24.69) | 341 (15.39) | 0.033# |
| RCA | 3,748 (31.56) | 729 (32.90) | 0.215 | 729 (39.64) | 729 (32.90) | <0.001# |
| Radial approach, % | 10,790 (91.95) | 1,969 (89.83) | 0.001# | 1,676 (92.09) | 1,969 (89.83) | 0.458 |
| Preprocedural TIMI flow grade | ||||||
| 0/1 | 2,022 (17.03) | 555 (25.05) | <0.001# | 383 (20.83) | 555 (25.05) | <0.001# |
| 2 | 1,100 (9.26) | 335 (15.12) | <0.001# | 199 (10.82) | 335 (15.12) | <0.001# |
| 3 | 8,753 (73.71) | 1,326 (59.84) | <0.001# | 1,429 (77.71) | 1,326 (59.84) | <0.001# |
| Postprocedural TIMI flow grade | ||||||
| 0/1 | 241 (2.03) | 103 (4.65) | <0.001# | 43 (2.34) | 103 (4.65) | 0.106 |
| 2 | 87 (0.73) | 30 (1.35) | 0.003# | 22 (1.20) | 30 (1.35) | <0.001# |
| 3 | 11,547 (97.24) | 2,083 (94.00) | <0.001# | 1,806 (98.21) | 2,083 (94.00) | <0.001# |
| Rotablation | 3 (0.03) | 57 (2.57) | <0.001# | 0 (0.00) | 57 (2.57) | <0.001# |
| Post-dilatation | 6,850 (62.69) | 1,361 (70.26) | <0.001# | 1,234 (69.80) | 1,361 (70.26) | <0.001# |
| IVUS usage, % | 539 (4.54) | 131 (5.91) | 0.005# | 96 (5.22) | 131 (5.91) | 0.010# |
| IABP usage, % | 88 (1.07) | 44 (2.39) | <0.001# | 32 (1.7) | 44 (2.39) | 0.164 |
| No. of stents | 1.00 (1.00, 2.00) | 2.00 (1.00, 2.00) | <0.001# | 2.00 (1.00, 2.00) | 2.00 (1.00, 2.00) | <0.001# |
| Stent diameter | 3.00 (2.73, 3.50) | 3.00 (2.67, 3.50) | 0.002# | 3.00 (2.75, 3.50) | 3.00 (2.67, 3.50) | 0.406 |
| Stent total length | 27.00 (18.00, 38.00) |
32.00 (23.00, 48.00) |
<0.001# | 29.00 (20.00, 43.00) |
32.00 (23.00, 48.00) |
<0.001# |
| Stent type | ||||||
| BMS, % | 0.00 (0.00, 0.00) | 0.00 (0.00, 0.00) | 0.187 | 0.00 (0.00, 0.00) | 0.00 (0.00, 0.00) | 0.132 |
| DES, % | 1.00 (1.00, 2.00) | 2.00 (1.00, 2.00) | <0.001# | 2.00 (1.00, 2.00) | 2.00 (1.00, 2.00) | <0.001# |
| PCI-related complication | ||||||
| No-reflow/slow flow | 328 (2.76) | 133 (6.00) | <0.001# | 64 (3.48) | 133 (6.00) | <0.001# |
| Perforation | 10 (0.09) | 8 (0.37) | 0.003# | 3 (0.17) | 8 (0.37) | 0.084 |
| Dissection | 115 (0.98) | 48 (2.18) | <0.001# | 27 (1.49) | 48 (2.18) | 0.002# |
Values are mean±SD or n (%). *Moderate/severe tortuosity defined as ≥3 consecutive curvatures of 90–180° measured at end-diastole in the target coronary artery. **Moderate/severe angulation defined as angulated target lesion with an angle >45°. #Indicate statistical significance. BMS, bare metal stent; DES, drug-eluting stent; IABP, intra-aortic balloon pump; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCX, left circumflex artery; LM, left main coronary artery; PCI, percutaneous coronary intervention; PSM, propensity score matching; RCA, right coronary artery; SYNTAX, SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery; TIMI, Thrombolysis in Myocardial Infarction.
All enrolled patients completed 2-year follow-up, and 9,221 (91.6%) patients completed the 5-year follow-up. At 2 years, patients with moderate/severe CAC had higher rates of cardiac death (1.1% vs. 0.6%, P=0.017), unplanned target vessel revascularization (TVR: 6.1% vs. 4.4%, P=0.002), definite/probable ST (0.9% vs. 0.4%, P=0.025) and MACE (9.0% vs. 6.7%, P<0.001) (Table 4). At 5 years, patients with moderate/severe CAC had higher rates of unplanned revascularization (15.2% vs. 13.2%, P=0.022) and MACE (20.7% vs. 17.9%, P=0.005) than patients with none/mild CAC (Table 5). Kaplan-Meier survival analysis yielded similar results for the primary endpoint (Figure 2) and secondary endpoints (Supplementary Figure 1). Landmark survival analyses revealed that the difference in the cumulative incidence of unplanned revascularization (0–1 year: log-rank P<0.0001; 1–5 years: log-rank P=0.5662) and MACE (0–1 year: log-rank P<0.0001; 1–5 years: log-rank P=0.6195) was most prominent in the first year after PCI, but became nonsignificant after the 1-year landmark (Supplementary Figure 2).
| Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|
| None/mild calcification (n=8,229) |
Moderate/severe calcification (n=1,839) |
P value | None/mild calcification (n=1,839) |
Moderate/severe calcification (n=1,839) |
P value | |
| Primary endpoint | ||||||
| MACE | 551 (6.7) | 166 (9.0) | <0.001# | 128 (7.0) | 166 (9.0) | 0.021# |
| Secondary endpoint | ||||||
| All-cause death | 96 (1.2) | 27 (1.5) | 0.287 | 29 (1.6) | 27 (1.5) | 0.788 |
| Cardiac death | 48 (0.6) | 20 (1.1) | 0.017# | 17 (0.9) | 20 (1.1) | 0.620 |
| Myocardial infarction | 140 (1.7) | 46 (2.5) | 0.021 | 38 (2.1) | 46 (2.5) | 0.377 |
| Unplanned TVR | 360 (4.4) | 112 (6.1) | 0.002# | 73 (4.0) | 112 (6.1) | 0.003# |
| ST | ||||||
| Definite | 14 (0.2) | 10 (0.5) | 0.007# | 2 (0.1) | 10 (0.5) | 0.021# |
| Probable | 28 (0.3) | 7 (0.4) | 0.790 | 9 (0.5) | 7 (0.4) | 0.616 |
| Possible | 25 (0.3) | 2 (0.1) | 0.210 | 11 (0.6) | 2 (0.1) | 0.012# |
| Definite/probable | 42 (0.5) | 17 (0.9) | 0.035# | 11 (0.6) | 17 (0.9) | 0.255 |
| Stroke | 107 (1.3) | 31 (1.7) | 0.199 | 25 (1.4) | 31 (1.7) | 0.419 |
| Bleeding | 127 (6.9) | 549 (6.7) | 0.717 | 128 (7.0) | 549 (6.7) | 0.948 |
#Indicate statistical significance. MACE, major adverse cardiac events; PSM, propensity score matching; ST, stent thrombosis; TVR, target vessel revascularization.
| Before PSM | After PSM | |||||
|---|---|---|---|---|---|---|
| None/mild calcification (n=8,229) |
Moderate/severe calcification (n=1,839) |
P value | None/mild calcification (n=1,839) |
Moderate/severe calcification (n=1,839) |
P value | |
| Primary endpoint | ||||||
| MACE | 1,475 (17.9) | 381 (20.7) | 0.005# | 336 (18.3) | 381 (20.7) | 0.061 |
| Secondary endpoint | ||||||
| All-cause death | 285 (3.5) | 79 (4.3) | 0.084 | 79 (4.3) | 79 (4.3) | 1.000 |
| Cardiac death | 168 (2.0) | 45 (2.4) | 0.275 | 50 (2.7) | 45 (2.4) | 0.603 |
| Myocardial infarction | 512 (6.2) | 117 (6.4) | 0.822 | 108 (5.9) | 117 (6.4) | 0.536 |
| Unplanned revascularization | 1,086 (13.2) | 280 (15.2) | 0.022# | 231 (12.6) | 280 (15.2) | 0.019# |
| Stroke | 287 (3.5) | 59 (3.2) | 0.552 | 71 (3.9) | 59 (3.2) | 0.284 |
| Bleeding | 1,116 (13.6) | 239 (13.0) | 0.521 | 251 (13.6) | 239 (13.0) | 0.560 |
#Indicate statistical significance. MACE, major adverse cardiac events; PSM, propensity score matching.
Kaplan-Meier survival analysis of 5-year MACE between moderate/severe CAC and none/mild CAC groups. CAC, coronary artery calcification; MACE, major adverse cardiac events.
After adjustment of confounding factors using Cox regression analysis with model 1, moderate/severe CAC was independently associated with a higher risk of 2-year unplanned TVR (HR=1.287, 95% CI: 1.036–1.600) and MACE (HR=1.242, 95% CI: 1.039–1.484), but not 5-year unplanned revascularization or MACE. Cox regression analysis using model 2 revealed a higher risk of unplanned revascularization at 5 years (HR=1.203, 95% CI: 1.007–1.438), as well as higher risk of MACE at 2 years (HR=1.208, 95% CI: 1.005–1.265) and 5 years (HR=1.147, 95% CI: 1.003–1.311) (Table 6).
| 2-year outcomes | 5-year outcomes | |||||
|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |||
| Model 1 | ||||||
| Primary outcome |  |
 |
||||
| MACE* | 1.242 (1.039–1.484) | 0.017# | 1.136 (0.980–1.316) | 0.090 | ||
| Secondary outcome | ||||||
| All-cause death | 1.040 (0.670–1.613) | 0.860 | 1.100 (0.800–1.512) | 0.557 | ||
| Cardiac death | 1.499 (0.870–2.583) | 0.144 | 0.904 (0.591–1.384) | 0.644 | ||
| MI | 1.340 (0.949–1.892) | 0.096 | 1.080 (0.836–1.397) | 0.556 | ||
| Unplanned revascularization** | 1.287 (1.036–1.600) | 0.023# | 1.161 (0.976–1.382) | 0.092 | ||
| Definite/probable ST*** | 1.137 (0.659–1.962) | 0.643 | – | – | ||
| Stroke | 1.144 (0.758–1.725) | 0.520 | 0.977 (0.811–1.176) | 0.804 | ||
| Model 2 | ||||||
| Primary outcome |  |
 |
||||
| MACE* | 1.203 (1.007–1.438) | 0.042# | 1.128 (1.005–1.265) | 0.040# | ||
| Secondary outcome | ||||||
| All-cause death | 0.995 (0.643–1.538) | 0.980 | 1.038 (0.805–1.338) | 0.775 | ||
| Cardiac death | 1.374 (0.803–2.351) | 0.246 | 0.983 (0.703–1.375) | 0.920 | ||
| MI | 1.304 (0.926–1.835) | 0.129 | 1.005 (0.819–1.234) | 0.958 | ||
| Unplanned revascularization** | 1.242 (0.999–1.545) | 0.051 | 1.147 (1.003–1.311) | 0.046# | ||
| Definite/probable ST*** | 1.147 (0.667–1.971) | 0.619 | ||||
| Stroke | 1.089 (0.723–1.641) | 0.683 | 0.801 (0.603–1.066) | 0.128 | ||
Results displayed are before propensity score matching. Adjusted variables: Model 1: age, sex, current smoker, diabetes, history of MI, history of CABG, renal failure age, sex, current smoker, diabetes, history of MI, history of CABG, renal failure; Model 2: age, sex, current smoker, diabetes, history of MI, history of CABG, renal failure, number of diseased vessels, pre-/postprocedural TIMI flow grade, no-reflow/slow reflow phenomenon. *MACE: composite event of all-cause death, MI and unplanned TVR in 2-year outcomes; composite event of all-cause death, MI and all unplanned revascularization in 5-year outcomes. **Unplanned revascularization refers to unplanned TVR in 2-year outcomes but all unplanned revascularizations in 5-year outcomes. ***ST events not recorded in 5-year outcomes. #Indicate statistical significance. Abbreviations as in Tables 1,3,4.
After propensity score matching, most matched baseline characteristics were no longer significantly different between groups (Table 1). In the matched population, patients with moderate/severe CAC had higher rates of unplanned TVR (2-year: 6.1% vs. 4.0%, P=0.003; 5-year: 15.2% vs. 12.6, P=0.019) and 2-year MACE (9.0% vs. 7.0%, P=0.021), whereas the occurrence of 5-year MACE became similar after propensity score matching (P>0.05) (Tables 4,5).
Subgroup AnalysisSubgroup analysis revealed that the effect of moderate/severe CAC on 2-year unplanned TVR and MACE was consistent across all subgroups except for diabetes, where a significant interaction was found (P for interaction=0.034) (Supplementary Tables 1, 2). In patients without diabetes, those with moderate/severe CAC were found to have a significantly higher risk of 2-year unplanned TVR than those with none/mild CAC (HR=1.691, 95% CI: 1.307–2.188). However, in patients with diabetes, there was only a trend towards higher risk of 2-year unplanned TVR in those with moderate/severe CAC.
In our prospective cohort study of Chinese patients undergoing PCI, we observed the following key findings. (1) Patients with moderate/severe CAC accounted for 18.3% of all patients undergoing PCI and tended to have worse baseline conditions and more comorbidities, including increased age, hypertension and history of CABG. (2) The incidence of complex angiographic features, more aggressive intervention and PCI-related complications was significantly higher in patients with moderate/severe CAC. (3) In the propensity matched analysis, patients with moderate/severe CAC had a significantly higher rate of 2-year unplanned TVR and MACE. At 5 years, however, the moderate/severe CAC population only had a higher rate of unplanned revascularization, and the rate of MACE was similar to that in patients with none/mild CAC. (4) Multivariate Cox regression analysis with clinically significant variables revealed moderate/severe CAC to be an independent predictor of 2-year unplanned TVR and MACE, but not of 5-year unplanned revascularization and MACE. (5) After adding procedural results to the multivariate model, CAC was shown to be an independent predictor of 2- and 5-year MACE, as well as 5-year unplanned revascularization.
CAC is a typical pathological change and a marker of significant coronary atherosclerosis. The prevalence of target lesion CAC detected by IVUS has been reported to exceed 70%.10 Although the underlying mechanism of CAC is not yet fully understood, de novo CAC is reported to be an active process stimulated by inflammatory pathways.15 For patients undergoing PCI, visual assessment of CAC is easily achievable through coronary angiography, but with relatively higher sensitivity for moderate/severe CAC and lower sensitivity for none/mild CAC,10 which could lead to underestimation of the prevalence of heavy CAC.10
In addition to angiographic assessment of CAC severity, CAC scoring is a cardiac computed tomography (CT)-based methodology to evaluate the amount of calcium within coronary arteries, the role of which in predicting long-term future clinical events in patients with and without coronary artery disease has been evaluated in previous studies.16–20 Although CAC scoring is a reliable, reproducible and predictive score of cardiovascular risk,21 it is dependent on results of cardiac CT. On the other hand, intravascular imaging techniques, including IVUS and optical coherence tomography (OCT), are considered as essential gold standards for coronary calcium detection.22 However, not all patients undergoing PCI have IVUS or OCT assessment during the procedure or have recently undergone cardiac CT scan. Thus, it is necessary to evaluate the patient’s long-term prognosis based on visual angiographical assessment of CAC in the absence of a CAC score.
A number of previous, similar studies of patients with moderate/severe CAC undergoing PCI have shown that such patients have an increased risk of death,9,23 revascularization,24 and MACE.9,23 Consistent with those studies, we found patients with moderate/severe CAC had a higher risk of 2-year unplanned TVR and MACE than those with none/mild CAC after adjusting for clinically significant risk factors (model 1). However, the difference in risk seemed to diminish to a nonsignificant level in the ensuing 5-year follow-up results. Furthermore, our landmark survival analysis also found that the cumulative incidence of unplanned revascularization and MACE differed most significantly before the 1-year landmark, after which the difference also became nonsignificant. In light of these dynamic risk changes, we propose the following possible mechanisms. (1) In our study, patients with moderate/severe CAC had more PCI-related complications, including no-reflow/slow reflow, perforation and dissection. In the early phase after procedure, these complications could result in an elevated risk of short-term unplanned TVR and MACE. (2) Moderate/severe CAC lesions give rise to stent under-expansion and strut malapposition, which are major risk factors for short- and mid-term in-stent restenosis and ST.25 (3) Patients with moderate/severe CAC also had a higher proportion of significant tortuosity and angulation. Delivering stents across such lesions can also lead to device-related complications, including stent entrapment, dislodgement, or polymer damage in drug-eluting stents. These complications might also compromise the short- and mid-term prognosis. (4) After high-risk stent implantation such as in moderate/severe CAC, delayed endothelial healing (even beyond 1 year) has been reported.26 It is therefore reasonable to infer that after 2 years endothelial function will be better restored. With better re-endothelialization, the risks of unplanned revascularization and MACE may decline to a nonsignificant level at 5 years.
After adding several variables reflecting severity of coronary disease and postprocedural outcomes to model 1, the adjusted results with model 2 revealed patients with moderate/severe CAC had a higher risk of MACE at both 2 and 5 years. Model 2 also revealed similarly significant effect of CAC on 2- and 5-year unplanned revascularization (although with borderline significance at 2 years). These results from model 2 suggested that the reduction in unplanned revascularization and MACE risk after 2 years (as shown with model 1) might be related to disease severity and procedural outcomes.
In the subgroup analysis, we observed a significant interaction between diabetes and moderate/severe CAC. However, the moderate/severe CAC group was found to have significantly higher risk of 2-year unplanned TVR than the none/mild CAC in patients without diabetes, although the risk was similar between these 2 CAC groups in patients with diabetes. This finding seems paradoxical, because diabetes is traditionally deemed to be a predictor of major adverse events in patients undergoing PCI.27 Possible explanations include: (1) the effect of diabetes on unplanned revascularization might be more profound than that of moderate/severe CAC. In other words, diabetic status elevated the risk of unplanned revascularization in patients with and without moderate/severe CAC, and hence the similar risk in the diabetes subgroup; (2) presumably, more patients with diabetes underwent CABG surgery after the index PCI procedure in our hospital. Because CABG is associated with lower rates of repeat revascularization as compared with PCI,28 rates of repeat revascularization might be lower in the diabetic subgroup; and (3) myocardial ischemia in patients with diabetes is often asymptomatic and frequently at an advanced stage when it becomes clinically manifest.29 Therefore some patients with diabetes might not be suitable for repeat revascularization when symptoms recur.
Study LimitationsOur study has several inherent limitations. First, in order to avoid sample size imbalance and improve comparisons, we did not divide our patients into 4 groups (no, mild, moderate and severe). Second, due to the observational design, our results are subject to unknown confounding factors, despite adjusting for known risk factors. Third, being a single-center study, the generalizability of our findings might be limited. Our patient population might be in better baseline condition compared with similar real-world studies, such as generally higher eGFR and zero patients with endstage renal disease requiring dialysis. Fourth, the severity of CAC was assessed by visual assessment of coronary angiography, which is inferior to intravascular imaging in terms of sensitivity and specificity. This could likely lead to underestimation of moderate/severe CAC. Fifth, our study enrolled patients in 2013 when rotablation was not widely used at our hospital (only ≈2.5% patients with moderate/severe CAC). We were unable to analyze the prognostic effect of rotablation due to limited case numbers. Furthermore, our subgroup analysis might be underpowered to confirm real-world interactions despite statistical significance.
Moderate/severe CAC was prevalent in our large cohort of Chinese patients undergoing PCI, and was an independent predictor of 2-year, but not 5-year unplanned TVR and MACE.
We give special thanks to the staff in the Department of Cardiology and Catheterization Laboratory, Fu Wai Hospital for their research contributions.
This study was supported by grants from Ministry of Science and Technology of the People’s Republic of China (2016YFC1301301) and National Natural Science Foundation of China (81,770,365).
The authors have no conflicts of interest to declare.
Ethics Committee of Fuwai Hospital; Reference no. 2017-860.
Supplementary Movie. Angiography videos reflecting each CAC severity.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0761
