Abstract
Background: Patients with peripheral arterial disease (PAD) or cerebrovascular disease (CeVD) are known to have worse outcomes when undergoing percutaneous coronary intervention (PCI) for coronary artery disease (CAD). Methods: We conducted a retrospective cohort study to investigate the impact of PAD and CeVD, and their various presentation subtypes on the clinical outcomes in patients undergoing PCI. 21,978 patients undergoing PCI at the Mount Sinai Hospital between 2012 and 2022 were stratified by the presence of PAD and/or CeVD and their most common presentation subtypes. Results: Among the cohorts 1,613 (7.3%) patients had PAD, 1,874 (8.5%) had CeVD and 453 (2.1%) had both (polyvascular group) while the CAD only (control group) 18,038 (82.1%) had neither. 1-year risk of MACCE was significantly higher for patients with PAD, CeVD or both where patients presenting with PAD and prior intervention and CeVD with past cerebrovascular accident (CVA) with hemiparesis had the highest risk among the various subgroups. Patients with a history of CVA with/without hemiparesis had a higher risk of stroke post PCI. Bleeding events were more frequent in polyvascular and PAD patients, on subgroup analysis only the PAD with prior intervention subgroup was statistically significant. Conclusion: PAD, CeVD and polyvascular disease demonstrate a higher risk of MACCE in patients undergoing PCI. This increased risk of MACCE appears to be driven by those with prior intervention or CVA with hemiparesis. An increased risk of bleeding is seen in patients with PAD, polyvascular disease and PAD with prior intervention when stratified by subgroup.
Keywords: Percutaneous coronary intervention, Coronary artery disease, Peripheral artery disease, Cerebrovascular disease, Adverse outcomes, Bleeding
1. INTRODUCTION
The prevalence of PAD and CeVD have been rising worldwide with global burden estimates of over 200 million and 100 million, respectively [1], [2], [3]. These patients often present with other high-risk comorbidities along with more complex coronary anatomy affecting procedural and long-term outcomes. Over the course of the past two decades newer techniques and devices have drastically improved the diagnosis and treatment of coronary artery disease (CAD) with endovascular therapy [4], [5], [6], [7], [8]. The improved accuracy in evaluation of disease anatomy and severity has allowed for a better assessment of risk in this high-risk patient population. Due to the multi-vascular nature of atherosclerosis, CAD often presents with overlapping peripheral artery disease (PAD) and cerebrovascular disease (CeVD). There is an increased risk of adverse outcomes and mortality in patients who had PAD [9], [10], [11], [12] or CeVD undergoing percutaneous coronary interventions (PCI) [13], [14], [15]. CeVD[13], [16], [17]. The combined presence of PAD and CeVD in patients undergoing PCI were associated with an even higher increased risk of in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) and bleeding [19], [20]. However, the relationship between the degree of disease of PAD and CeVD on PCI outcomes is yet to be established. This study aims to shed further insight on the impact of PAD and CeVD severity in PCI patients by evaluating major adverse cardiovascular events (MACCE) and bleeding events in various PAD and CeVD subcategories up to 1-year post PCI.
2. METHODS
Study Population
Consecutive patients who underwent percutaneous coronary intervention (PCI) at the Mount Sinai Hospital between January 2012 and December 2022 were included for this retrospective cohort study. Patients who did not undergo stenting, had missing key covariate data or lacking follow-up at 1 year were excluded. Data on baseline medical conditions and procedural characteristics were collected through chart review from electronic medical records. Diagnoses were ascertained using data from our Cath reports and electronic health records, including problem lists and discharge diagnoses coded by treating clinicians. Follow-up information and adverse event data was recorded through medical record review, clinic visits or phone calls made by trained research personnel up to 1-year post procedure. All patients provided written consent prior to inclusion in the registry, and the registry was approved by the local Institutional Review Board.
CAD patients undergoing PCI were stratified into those who also had a diagnosis of PAD, CeVD or both PAD and CeVD (polyvascular group) and those with CAD only (control group). Further sub stratification of PAD and CeVD was done into subcategories based on presentation prior to PCI. PAD was divided into 2 groups (PAD without prior intervention) and (PAD with prior intervention). Prior intervention was defined as history of vascular surgery or PTA. Patients with history of only amputation were excluded from subgroup analysis due to lack of information on cause of amputation. Apart from smaller subgroups diagnosed by objective testing (ABI < 0.9 or invasive imaging demonstrating ≥ 50% stenosis), there was no universal requirement for confirmatory imaging for diagnosis of PAD. CeVD was divided into 3 groups (CeVD and cerebrovascular accident (CVA) without residual deficit), (CeVD and TIA) and (CeVD and CVA with hemiparesis). Due to limited statistical power the smaller subgroups were excluded from subgroup analysis.
Endpoints.
The primary outcome was major adverse cardiovascular events (MACCE) at 1 year, defined as a composite of All-cause mortality, Myocardial infarction (MI) and Stroke. MI and stroke definitions were taken from the ACC NCDR CathPCI Registry data dictionary v4.4 (18). Secondary outcomes included target vessel revascularization, individual MACCE components and bleeding at 1 year. Bleeding was defined as any in-hospital or post discharge bleeding with a hemoglobin drop of > 3 g or requiring transfusion, intervention or hospitalization.
2.1. Statistical analysis
Baseline characteristics were compared using chi-squared and Student’s t-tests and reported as (mean 土 standard deviation) or count with percentage. Time-to-event outcomes were assessed with Kaplan-Meier estimates and compared using log-rank tests. Cox multivariate regression models were used to estimate hazard ratios (HR) for outcomes at 1 year. Patients with neither PAD nor CeVD were used as reference group for all cohorts. Models were adjusted for age, sex, race, chronic kidney disease, diabetes, prior myocardial infarction (MI), acute coronary syndrome (ACS) at presentation, multi-vessel disease, moderate or severe calcification and anticoagulant use at discharge. Proportional hazards assumptions were verified. All risks were expressed as hazard ratio (HR) with 95% confidence interval (CI), a p-value of < 0.05 was considered statistically significant. All statistical analyses were conducted at the Icahn School of Medicine at Mount Sinai, New York, NY, using Stata software version 18.0 (StataCorp) and SAS version 9.4 (SAS Institute, Inc).
3. RESULTS
A total of 21,978 patients undergoing PCI for CAD were included in the final analysis. Among the cohorts 1,613 (7.3%) patients had PAD, 1,874 (8.5%) had CeVD and 453 (2.1%) had both (polyvascular group) while the CAD only (control group) 18,038 (82.1%) had neither Table 1. The selection of study participants is shown in Fig. 1. The PAD without prior intervention subgroup included 437 (27.1%) patients presenting with claudication and the PAD with prior intervention subgroup had 570 (35.3%) patients with history of prior vascular surgery or PTA. Among the CVA subgroups 609 (32.5%) had CVA without residual deficit, 328 (17.5%) had CVA with hemiparesis and 483 (25.8%) had prior TIA Table 1.
Table 1.
(Baseline characteristics).
|
CAD only N = 18038(82.1%) |
PAD N = 1613(7.3%) |
CeVD N = 1874(8.5%) |
Polyvascular (PAD & CeVD) N = 453(2.1%) |
P-value | |
|---|---|---|---|---|---|
| Age, years | 65.8 ± 11.5 | 69.3 ± 10.3 | 69.7 ± 10.9 | 71.2 ± 10.0 | 0<.001 |
| BMI, kg/m2 | 28.8 ± 5.6 | 28.8 ± 5.7 | 28.6 ± 5.7 | 28.0 ± 6.1 | 0.012 |
| Female sex | 4904 (27.2%) | 513 (31.8%) | 687 (36.7%) | 168 (37.1%) | 0<.001 |
| Race/ethnicity | 0<.001 | ||||
| Caucasian | 7817 (43.3%) | 642 (39.8%) | 756 (40.3%) | 216 (47.7%) | |
| African American | 1606 (8.9%) | 229 (14.2%) | 261 (13.9%) | 66 (14.6%) | |
| Asian | 2802 (15.5%) | 111 (6.9%) | 222 (11.8%) | 20 (4.4%) | |
| Hispanic | 2684 (14.9%) | 395 (24.5%) | 322 (17.2%) | 91 (20.1%) | |
| Others | 3129 (17.3%) | 236 (14.6%) | 313 (16.7%) | 60 (13.2%) | |
| Medical history | |||||
| Current smoker | 2243 (12.4%) | 288 (17.9%) | 188 (10.0%) | 78 (17.2%) | 0<.001 |
| Family history of CAD | 3597 (19.9%) | 271 (16.8%) | 333 (17.8%) | 77 (17.0%) | 0.002 |
| Anemia | 6179 (36.1%) | 814 (52.9%) | 888 (49.5%) | 266 (60.7%) | 0<.001 |
| Diabetes Mellitus | 8116 (45.0%) | 981 (60.8%) | 1055 (56.3%) | 275 (60.7%) | 0<.001 |
| Insulin dependent | 2633 (32.4%) | 468 (47.7%) | 396 (37.5%) | 133 (48.4%) | 0<.001 |
| Hypertension | 16,421 (91.0%) | 1556 (96.5%) | 1802 (96.2%) | 439 (96.9%) | 0<.001 |
| Hyperlipidemia | 16,261 (90.2%) | 1526 (94.6%) | 1773 (94.6%) | 429 (94.7%) | 0<.001 |
| Lung disease | 1076 (6.0%) | 210 (13.0%) | 175 (9.3%) | 64 (14.1%) | 0<.001 |
| Peripheral artery disease | 0 (0.0%) | 1565 (97.0%) | 0 (0.0%) | 435 (96.0%) | N/A |
| Cerebrovascular disease | 0 (0.0%) | 0 (0.0%) | 1837 (98.0%) | 438 (96.7%) | N/A |
| Atrial fibrillation | 1360 (7.5%) | 181 (11.2%) | 252 (13.4%) | 66 (14.6%) | 0<.001 |
| Dialysis | 539 (3.0%) | 127 (7.9%) | 119 (6.4%) | 44 (9.7%) | 0<.001 |
| Chronic kidney disease | 4451 (24.7%) | 637 (39.5%) | 700 (37.4%) | 230 (50.8%) | 0<.001 |
| Prior PCI | 6610 (36.6%) | 715 (44.3%) | 738 (39.4%) | 198 (43.7%) | 0<.001 |
| Prior MI | 3538 (19.6%) | 382 (23.7%) | 458 (24.4%) | 132 (29.1%) | 0<.001 |
| Prior CABG | 2453 (13.6%) | 430 (26.7%) | 381 (20.3%) | 144 (31.8%) | 0<.001 |
| LVEF, % | 54.6 ± 11.0 | 53.0 ± 12.2 | 53.5 ± 11.6 | 0<.001 | |
| PCI presentation | |||||
| Asymptomatic | 779 (4.3%) | 59 (3.7%) | 79 (4.2%) | 28 (6.2%) | 0.135 |
| Stable angina | 9723 (53.9%) | 925 (57.3%) | 1003 (53.5%) | 223 (49.2%) | 0.009 |
| Unstable angina | 4454 (24.7%) | 372 (23.1%) | 481 (25.7%) | 109 (24.1%) | 0.343 |
| NSTEMI | 2194 (12.2%) | 202 (12.5%) | 239 (12.8%) | 74 (16.3%) | 0.056 |
| STEMI | 614 (3.4%) | 26 (1.6%) | 29 (1.5%) | 9 (2.0%) | 0<.001 |
| Laboratory | |||||
| HbA1c, % | 7.2 ± 1.7 | 7.4 ± 1.8 | 7.3 ± 1.6 | 7.2 ± 1.6 | 0<.001 |
| Glucose, mg/dL | 136.9 ± 71.6 | 149.3 ± 86.5 | 141.2 ± 69.9 | 154.9 ± 108.3 | 0<.001 |
| Serum creatinine, mg/dL | 1.2 ± 1.0 | 1.5 ± 1.5 | 1.4 ± 1.3 | 1.7 ± 1.6 | 0<.001 |
| Hemoglobin, g/dL | 13.1 ± 1.8 | 12.4 ± 1.9 | 12.5 ± 1.8 | 12.0 ± 1.9 | 0<.001 |
| Platelets, per mm3 | 212.6 ± 72.9 | 213.6 ± 90.2 | 210.6 ± 75.8 | 213.2 ± 79.0 | 0.684 |
| Total cholesterol, mg/dL | 141.8 ± 41.9 | 137.5 ± 45.1 | 137.9 ± 44.4 | 137.0 ± 40.5 | 0<.001 |
| Triglycerides, mg/dL | 104.9 ± 83.2 | 108.3 ± 102.5 | 102.3 ± 68.6 | 107.0 ± 77.4 | 0.204 |
| Low density lipoprotein, mg/dL | 82.0 ± 32.5 | 78.5 ± 31.7 | 78.7 ± 32.1 | 77.1 ± 30.8 | 0<.001 |
| High density lipoprotein, mg/dL | 40.2 ± 12.0 | 39.1 ± 11.9 | 40.1 ± 12.0 | 40.7 ± 12.4 | 0.010 |
| hsCRP, mg/L | 2.4 ± 2.2 | 2.9 ± 2.4 | 2.6 ± 2.3 | 3.1 ± 2.4 | 0<.001 |
| Troponin, ng/mL | 1.2 ± 9.4 | 1.2 ± 10.5 | 0.8 ± 4.8 | 1.0 ± 4.2 | 0.315 |
| Creatine kinase-MB, IU/L | 6.7 ± 25.9 | 4.7 ± 19.1 | 3.9 ± 12.2 | 4.5 ± 15.0 | 0<.001 |
| Admission medication | |||||
| Aspirin | 15,732 (87.2%) | 1422 (88.2%) | 1622 (86.6%) | 414 (91.4%) | 0.030 |
| Beta blocker | 12,301 (68.2%) | 1205 (74.7%) | 1402 (74.8%) | 346 (76.4%) | 0<.001 |
| Calcium channel blockers | 6110 (33.9%) | 701 (43.5%) | 815 (43.5%) | 211 (46.6%) | 0<.001 |
| Coumadin | 363 (2.0%) | 60 (3.7%) | 98 (5.2%) | 20 (4.4%) | 0<.001 |
| P2y12-inhibitors | 6742 (37.4%) | 838 (52.0%) | 903 (48.2%) | 279 (61.6%) | 0<.001 |
| Clopidogrel | 5354 (29.7%) | 743 (46.1%) | 829 (44.2%) | 254 (56.1%) | 0<.001 |
| Prasugrel | 496 (2.7%) | 45 (2.8%) | 27 (1.4%) | 8 (1.8%) | 0.005 |
| Ticagrelor | 898 (5.0%) | 52 (3.2%) | 50 (2.7%) | 17 (3.8%) | 0<.001 |
| Procedural characteristics | |||||
| Radial access | 4121 (22.8%) | 356 (22.1%) | 358 (19.1%) | 88 (19.4%) | 0.001 |
| Femoral access | 13,618 (75.5%) | 1209 (75.0%) | 1487 (79.3%) | 351 (77.5%) | 0.002 |
| PCI vessels | |||||
| Left main | 1130 (6.3%) | 176 (10.9%) | 152 (8.1%) | 65 (14.3%) | 0<.001 |
| LAD | 11,057 (61.3%) | 918 (56.9%) | 1141 (60.9%) | 267 (58.9%) | 0.006 |
| LCX | 7713 (42.8%) | 771 (47.8%) | 867 (46.3%) | 235 (51.9%) | 0<.001 |
| RCA | 7367 (40.8%) | 770 (47.8%) | 821 (43.8%) | 204 (45.0%) | 0<.001 |
| SVG | 486 (2.7%) | 85 (5.3%) | 84 (4.5%) | 35 (7.7%) | 0<.001 |
| Multi-vessel disease | 11,430 (63.4%) | 1193 (74.0%) | 1325 (70.7%) | 361 (79.7%) | 0<.001 |
| Lesion profile | |||||
| B2/C lesion | 13,028 (72.2%) | 1191 (73.8%) | 1358 (72.5%) | 352 (77.7%) | 0.041 |
| Moderate to Severe calcification | 3769 (21.0%) | 441 (27.5%) | 511 (27.4%) | 151 (33.3%) | 0<.001 |
| Bifurcation | 3547 (19.7%) | 271 (16.8%) | 312 (16.6%) | 75 (16.6%) | 0<.001 |
| Chronic total occlusion | 1234 (6.8%) | 100 (6.2%) | 98 (5.2%) | 20 (4.4%) | 0.010 |
| Total lesion length, mm | 28.3 ± 18.7 | 28.4 ± 18.1 | 28.0 ± 17.9 | 29.7 ± 20.5 | 0.356 |
| No. of lesions treated | 1.3 ± 0.6 | 1.3 ± 0.6 | 1.3 ± 0.6 | 1.3 ± 0.6 | 0.201 |
| Stent profile | |||||
| Bare metal stent | 18 (0.1%) | 5 (0.3%) | 7 (0.4%) | 1 (0.2%) | 0.005 |
| Drug eluting stent | 16,769 (93.0%) | 1521 (94.3%) | 1744 (93.1%) | 420 (92.7%) | 0.245 |
| Total stent length, mm | 34.1 ± 21.6 | 34.7 ± 22.7 | 33.8 ± 21.3 | 34.9 ± 21.7 | 0.656 |
| No. of stents implanted | 1.5 ± 0.7 | 1.5 ± 0.7 | 1.5 ± 0.7 | 1.5 ± 0.7 | 0.494 |
| Maximum stent diameter, mm | 3.1 ± 0.5 | 3.1 ± 0.5 | 3.1 ± 0.5 | 3.1 ± 0.5 | 0.783 |
| Pre-procedural TIMI flow | 2.6 ± 0.9 | 2.7 ± 0.8 | 2.7 ± 0.8 | 2.7 ± 0.8 | 0<.001 |
| Post-procedural TIMI flow | 3.0 ± 0.2 | 3.0 ± 0.2 | 3.0 ± 0.2 | 3.0 ± 0.2 | 0.159 |
| Syntax score | 13.5 ± 10.2 | 15.5 ± 11.9 | 14.8 ± 11.4 | 17.4 ± 12.8 | 0<.001 |
| Complex PCIa | 6197 (39.5%) | 613 (42.4%) | 664 (39.6%) | 191 (46.2%) | 0.008 |
| Discharge medication | |||||
| DAPT | 16,922 (94.2%) | 1452 (90.9%) | 1695 (91.0%) | 399 (88.7%) | 0<.001 |
| Aspirin | 16,985 (94.5%) | 1456 (91.1%) | 1701 (91.4%) | 401 (89.1%) | 0<.001 |
| P2y12-inhibitors | 17,841 (99.3%) | 1589 (99.4%) | 1847 (99.2%) | 446 (99.1%) | 0.821 |
| Clopidogrel | 12,525 (69.7%) | 1270 (79.5%) | 1596 (85.7%) | 375 (83.3%) | 0<.001 |
| Prasugrel | 2100 (11.7%) | 119 (7.4%) | 42 (2.3%) | 15 (3.3%) | 0<.001 |
| Ticagrelor | 3288 (18.3%) | 202 (12.6%) | 214 (11.5%) | 57 (12.7%) | 0<.001 |
| Anticoagulants | 1316 (7.3%) | 201 (12.6%) | 278 (15.0%) | 70 (15.6%) | 0<.001 |
| Statin | 17,130 (95.3%) | 1525 (95.4%) | 1754 (94.2%) | 424 (94.2%) | 0.128 |
| Beta blocker | 14,337 (79.8%) | 1305 (81.7%) | 1510 (81.1%) | 365 (81.1%) | 0.166 |
| Cerebrovascular disease | |||||
| Carotid stenosis > 79% | 0 (0.0%) | 0 (0.0%) | 88 (4.7%) | 45 (9.9%) | |
| Prior carotid endarterectomy | 0 (0.0%) | 0 (0.0%) | 128 (6.8%) | 50 (11.0%) | |
| Carotid stenosis > 50% not < 79% | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| CVA without residual deficit | 0 (0.0%) | 0 (0.0%) | 609 (32.5%) | 136 (30.0%) | |
| TIA | 0 (0.0%) | 0 (0.0%) | 483 (25.8%) | 96 (21.2%) | |
| CVA with hemiparesis | 0 (0.0%) | 0 (0.0%) | 328 (17.5%) | 65 (14.3%) | |
| CVA with hemiplegia | 0 (0.0%) | 0 (0.0%) | 34 (1.8%) | 7 (1.5%) | |
| CVA with dysphagia | 0 (0.0%) | 0 (0.0%) | 12 (0.6%) | 5 (1.1%) | |
| Prior carotid Artery Stent | 0 (0.0%) | 0 (0.0%) | 42 (2.2%) | 17 (3.8%) | |
| CVA with residual deficit | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Overall | 0 (0.0%) | 0 (0.0%) | 1874 (100%) | 453 (100%) | |
| Peripheral artery disease | |||||
| Claudication | 0 (0.0%) | 437 (27.1%) | 0 (0.0%) | 92 (20.3%) | |
| Amputation | 0 (0.0%) | 114 (7.1%) | 0 (0.0%) | 24 (5.3%) | |
| Vascular bypass or PTA | 0 (0.0%) | 570 (35.3%) | 0 (0.0%) | 177 (39.1%) | |
| Documented aortic aneurysm repair | 0 (0.0%) | 46 (2.9%) | 0 (0.0%) | 14 (3.1%) | |
| ABI < 0.9 | 0 (0.0%) | 44 (2.7%) | 0 (0.0%) | 14 (3.1%) | |
| Invasive testing > 50% stenosis | 0 (0.0%) | 82 (5.1%) | 0 (0.0%) | 33 (7.3%) | |
| Overall | 0 (0.0%) | 1613 (100%) | 0 (0.0%) | 453 (100%) |
BMI: body mass index, CAD: coronary artery disease, PAD: peripheral artery disease, CeVD/CVD: cerebrovascular disease, TIA: transient ischemic attack, CVA: cerebrovascular accident, PTA: percutaneous transluminal angioplasty PCI: percutaneous coronary intervention, MI: myocardial infarction, CABG: coronary artery bypass grafting, LVEF: left ventricular ejection fraction, NSTEMI: non-ST segment elevation myocardial infarction, LAD: Left anterior descending, LCX: Left circumflex, RCA: Right coronary artery, SVG: saphenous vein graft, DAPT: dual antiplatelet therapy.
PCI is considered complex if fulfilling any of these criteria: total stent length ≥ 60 mm, total number of stents implanted ≥ 3, total number of lesions ≥ 3, total number of target vessels ≥ 3, bifurcation lesion with ≥ 2 stents, and chronic total occlusion
Fig. 1.
(Study population flowchart): Flowchart demonstrating patient selection, exclusions and final study population included for analysis.
CAD patients with PAD, CeVD or both were significantly older the CAD only patients (69.3, 69.7 & 71.2 vs. 65.8 years, p < 0.001), and more frequently female Table 1. PAD, CeVD and polyvascular group patients had a higher prevalence of comorbidities, prior cardiovascular events and were also more likely to have history of prior PCI, CABG or MI Table 1. More lesions in the PAD, CeVD or polyvascular groups were associated with calcification and those in control group had more bifurcation lesions. On admission more than twice the number of patients in the control group presented with STEMI compared to PAD, CeVD or polyvascular groups. Access site bleeding 34 (0.2%) remained very low among all groups despite the continuation of a femoral dominant approach in our center throughout the duration of our study. Other procedural characteristics remained comparable between the various groups Table 1.
On admission a higher number of patients in PAD, CeVD or polyvascular groups were on antiplatelet or anticoagulant medications, anti-hypertensive medications and statins Table 1. On discharge patients with CAD only, had higher use of DAPT, aspirin, ticagrelor and prasugrel whereas PAD, CeVD and polyvascular group patients had higher use of clopidogrel and anticoagulants with comparable statin use Table 1.
Association between PAD or CeVD subcategories and individual MACCE components and bleeding at 1 year are reported in Table 2. PAD with prior intervention had the highest risk of death (6.7% adj. HR 1.64 95% CI 1.13–2.39, p = 0.009) followed by CeVD and CVA with hemiparesis (6.3% adj. HR 1.66 95% CI 1.01–2.74, p = 0.046). CeVD patients with a history of CVA with/without residual deficit had increased risk of stroke. CeVD and CVA with hemiparesis also had higher risk of MI. All bleeding was only significant in the PAD with prior intervention subgroup (7.7% adj. HR 1.35 95% CI 1.01–1.81, p = 0.046). CeVD patients with a history of CVA with hemiparesis (11.8% adj. HR 1.87 95% CI 1.32–2.65, p < 0.001) and PAD with prior intervention (10.1% adj. HR 1.40 95% CI 1.05–1.87, p = 0.022) had a higher risk of MACCE. All other subcategories of PAD and CeVD had comparable association with MACCE and bleeding or did not reach statistical significance.
Table 2.
(Adjusted associations between PAD or CeVD subgroups and individual MACCE components and bleeding at 1 year).
| Events (%) | Hazard Ratio | P-Value | AdjustedHazard Ratio | P-Valuea | |
|---|---|---|---|---|---|
| All-cause death | |||||
| No PAD, No CVD | 360 (2.0%) | Ref. | |||
| CVD and CVA without residual deficit | 35 (5.6%) | 2.42 (1.71–––3.43) | 0<.001 | 1.33 (0.87–––2.03) | 0.182 |
| CVD and TIA | 18 (3.6%) | 1.60 (1.00–––2.57) | 0.051 | 1.02 (0.60–––1.73) | 0.941 |
| CVD and CVA with hemiparesis | 20 (6.3%) | 2.70 (1.72–––4.24) | 0<.001 | 1.66 (1.01–––2.74) | 0.046 |
| PAD and vascular bypass or PTA | 41 (6.7%) | 2.89 (2.10–––4.00) | 0<.001 | 1.64 (1.13–––2.39) | 0.009 |
| PAD and claudication | 19 (4.3%) | 1.82 (1.15–––2.88) | 0.011 | 1.19 (0.70–––2.01) | 0.521 |
| MI | |||||
| No PAD, No CVD | 284 (1.6%) | Ref. | |||
| CVD and CVA without residual deficit | 13 (2.3%) | 1.14 (0.65–––1.99) | 0.646 | 0.78 (0.45–––1.37) | 0.387 |
| CVD and TIA | 18 (3.9%) | 2.04 (1.27–––3.28) | 0.003 | 1.43 (0.88–––2.32) | 0.144 |
| CVD and CVA with hemiparesis | 22 (7.1%) | 3.83 (2.48–––5.91) | 0<.001 | 2.43 (1.56–––3.80) | 0<.001 |
| PAD and vascular bypass or PTA | 25 (4.3%) | 2.25 (1.49–––3.39) | 0<.001 | 1.33 (0.88–––2.03) | 0.180 |
| PAD and claudication | 16 (3.7%) | 1.95 (1.18–––3.22) | 0.010 | 1.29 (0.77–––2.15) | 0.328 |
| Stroke | |||||
| No PAD, No CVD | 44 (0.2%) | Ref. | |||
| CVD and CVA without residual deficit | 7 (1.2%) | 3.99 (1.80–––8.86) | 0<.001 | 3.00 (1.33–––6.77) | 0.008 |
| CVD and TIA | 3 (0.7%) | 2.19 (0.68–––7.05) | 0.189 | 1.58 (0.48–––5.14) | 0.451 |
| CVD and CVA with hemiparesis | 4 (1.4%) | 4.46 (1.60–––12.4) | 0.004 | 3.09 (1.07–––8.88) | 0.037 |
| PAD and vascular bypass or PTA | 1 (0.1%) | 0.58 (0.08–––4.20) | 0.589 | 0.37 (0.05–––2.71) | 0.326 |
| PAD and claudication | 2 (0.5%) | 1.57 (0.38–––6.48) | 0.533 | 1.12 (0.27–––4.70) | 0.877 |
| All bleeding | |||||
| No PAD, No CVD | 755 (4.2%) | Ref. | |||
| CVD and CVA without residual deficit | 49 (6.9%) | 1.59 (1.19–––2.12) | 0.002 | 1.15 (0.84–––1.59) | 0.377 |
| CVD and TIA | 31 (5.5%) | 1.29 (0.90–––1.85) | 0.165 | 1.04 (0.71–––1.51) | 0.845 |
| CVD and CVA with hemiparesis | 31 (8.4%) | 1.92 (1.34–––2.75) | 0<.001 | 1.34 (0.91–––1.98) | 0.140 |
| PAD and vascular bypass or PTA | 56 (7.7%) | 1.83 (1.39–––2.40) | 0<.001 | 1.35 (1.01–––1.81) | 0.046 |
| PAD and claudication | 33 (6.4%) | 1.50 (1.06–––2.13) | 0.022 | 1.30 (0.89–––1.88) | 0.170 |
| MACCE | |||||
| No PAD, No CVD | 642 (3.6%) | Ref. | |||
| CVD and CVA without residual deficit | 50 (8.1%) | 1.94 (1.46–––2.59) | 0<.001 | 1.13 (0.81–––1.57) | 0.471 |
| CVD and TIA | 36 (7.4%) | 1.81 (1.29–––2.53) | 0<.001 | 1.24 (0.87–––1.77) | 0.229 |
| CVD and CVA with hemiparesis | 38 (11.8%) | 2.94 (2.12–––4.08) | 0<.001 | 1.87 (1.32–––2.65) | 0<.001 |
| PAD and vascular bypass or PTA | 62 (10.1%) | 2.47 (1.90–––3.20) | 0<.001 | 1.40 (1.05–––1.87) | 0.022 |
| PAD and claudication | 35 (8.0%) | 1.88 (1.34–––2.65) | 0<.001 | 1.24 (0.86–––1.78) | 0.256 |
CI: confidence interval, MI: myocardial infarction, TVR: target vessel revascularization
The percentages mentioned above represent K-M rates at 12 months after index procedure.
Model adjusted for age, sex, race, chronic kidney disease, diabetes, prior MI, ACS, multi-vessel disease, moderate or severe calcification and anticoagulant at discharge.
Adjusted associations between PAD or CeVD and MACCE components and bleeding at 1-year are reported in Table 3. PAD patients had an increased risk of death, MI and bleeding. CeVD patients had an increased risk of MI and stroke. Polyvascular patients had an increased risk of death, stroke and bleeding. Risk of MACCE at 1 year was significantly higher in patients with PAD (9.4% adj. HR 1.55 95% CI 1.26–1.91, p < 0.001), CeVD (7.9% adj. HR 1.36 95% CI 1.10–1.68, p = 0.005) or both (10.8% adj. HR 1.43 95% CI 1.02–2.00, p = 0.039), when compared to patients with neither (4.1%) Fig. 2.
Table 3.
(Adjusted associations between PAD or CeVD and MACCE components and bleeding at 1 year).
| No. of patients | No. of event (%) | HR(95% CI) | p-value |
Adjusted HR (95% CI)* |
p-value | Trend p-value | |
|---|---|---|---|---|---|---|---|
| All-cause death | |||||||
| No PAD, No CeVD | 18,038 | 360 (2.3%) | Ref. | Ref. | 0<.001 | ||
| PAD | 1613 | 78 (5.7%) | 2.51 (1.97–––3.21) | 0<.001 | 1.69 (1.28–––2.24) | 0<.001 | |
| CeVD | 1874 | 63 (4.0%) | 1.75 (1.34–––2.29) | 0<.001 | 1.13 (0.82–––1.55) | 0.459 | |
| PAD and CeVD | 453 | 31 (8.2%) | 3.59 (2.49–––5.18) | 0<.001 | 1.88 (1.26–––2.82) | 0.002 | |
| MI | |||||||
| No PAD, No CeVD | 18,038 | 284 (1.8%) | Ref. | Ref. | 0<.001 | ||
| PAD | 1613 | 55 (4.3%) | 2.26 (1.69–––3.01) | 0<.001 | 1.60 (1.19–––2.16) | 0.002 | |
| CeVD | 1874 | 56 (3.9%) | 1.98 (1.49–––2.64) | 0<.001 | 1.51 (1.12–––2.02) | 0.006 | |
| PAD and CeVD | 453 | 14 (3.9%) | 2.07 (1.21–––3.55) | 0.008 | 1.15 (0.67–––1.98) | 0.616 | |
| Stroke | |||||||
| No PAD, No CeVD | 18,038 | 44 (0.3%) | Ref. | Ref. | 0<.001 | ||
| PAD | 1613 | 3 (0.2%) | 0.79 (0.25–––2.55) | 0.696 | 0.61 (0.19–––1.99) | 0.415 | |
| CeVD | 1874 | 13 (0.9%) | 2.97 (1.60–––5.51) | 0<.001 | 2.39 (1.27–––4.50) | 0.007 | |
| PAD and CeVD | 453 | 5 (1.4%) | 4.77 (1.89–––12.0) | 0<.001 | 3.38 (1.31–––8.73) | 0.012 | |
| All bleeding | |||||||
| No PAD, No CeVD | 18,038 | 755 (4.3%) | Ref. | Ref. | 0<.001 | ||
| PAD | 1613 | 103 (6.6%) | 1.55 (1.26–––1.90) | 0<.001 | 1.29 (1.04–––1.60) | 0.023 | |
| CeVD | 1874 | 116 (6.5%) | 1.50 (1.23–––1.82) | 0<.001 | 1.18 (0.95–––1.45) | 0.126 | |
| PAD and CeVD | 453 | 45 (10.3%) | 2.42 (1.79–––3.27) | 0<.001 | 1.56 (1.13–––2.17) | 0.008 | |
| MACCE | |||||||
| No PAD, No CeVD | 18,038 | 642 (4.1%) | Ref. | Ref. | 0<.001 | ||
| PAD | 1613 | 126 (9.4%) | 2.29 (1.89–––2.77) | 0<.001 | 1.55 (1.26–––1.91) | 0<.001 | |
| CeVD | 1874 | 122 (7.9%) | 1.91 (1.58–––2.32) | 0<.001 | 1.36 (1.10–––1.68) | 0.005 | |
| PAD and CeVD | 453 | 41 (10.8%) | 2.69 (1.96–––3.69) | 0<.001 | 1.43 (1.02–––2.00) | 0.039 | |
CI: confidence interval, MI: myocardial infarction, TVR: target vessel revascularization
† Model adjusted for age, sex, race, chronic kidney disease, diabetes, prior MI, ACS, multi-vessel disease, moderate or severe calcification and anticoagulant at discharge.
The percentages mentioned above represent K-M rates at 12 months after index procedure.
Fig. 2.
(Adjusted risk of MACCE at 1 year): Adjusted Kaplan–Meier curves demonstrating the cumulative incidence of MACCE at 1 year among PCI patients with PAD, CeVD, and CAD only.
4. DISCUSSION
The key findings of our analysis on adverse outcomes in various subgroups of patients with PAD, CeVD or both compared to those with neither are as follows. First, patients with CAD and CeVD, PAD or both had more advanced comorbidities, higher degree of CAD complexity, and higher rate of prior procedures including PCI, CABG and PTA or Vascular surgery. Second, MACCE rates at 1-year post PCI were higher in the PAD, CeVD and polyvascular groups with the polyvascular group having the highest risk. CeVD or CVA with hemiparesis had the highest contribution among any of the various presentation subtypes. All subgroups of CeVD had higher rates of stroke on follow-up. Third, an increase in bleeding was seen in the PAD and polyvascular groups with statistical significance being reached only in the PAD with history of prior intervention subgroup when stratified by presentation subtype.
It has been well established in various prior studies such as the REACH registry among others that patients with PAD and CeVD have a higher burden of comorbidities [19], [21], [22], [23]. The global REACH registry reported that patients with PAD and CeVD had higher association with diabetes and hypertension although CAD patients had a higher burden of hypercholesterolemia. We observed that hypercholesterolemia was higher in PAD, CeVD and polyvascular groups, this difference may be explained by the inclusion of multiple geographic groups from across the world in the REACH registry opposed to our single center analysis in the New York area. It should also be noted that this data was published in 2006 when PAD and CeVD were still under diagnosed compared to present day.
The higher event rates in patients who present with prior history of revascularization in the PAD and CeVD arm is supported by prior studies [10], [22], [24], [25], [26], [27], [28], [29]. The findings of Subherwal et al. suggest that the risk of adverse outcomes increases with the number of vascular beds involved in polyvascular disease. They also found that patients with PAD and CeVD were less likely to undergo guideline directed therapy and coronary revascularization (22). On admission we saw that patients in the CAD only group presented with STEMI more often than the patients in PAD, CeVD or polyvascular groups, presentation with NSTEMI was comparable between all groups. Prior studies reported that patients with a diagnosis of prior vascular disease were more likely to present with NSTEMI as opposed to STEMI, where less likely to undergo revascularization and had higher mortality [17], [26]. This may be explained by more regular follow-up monitoring of CeVD patients after diagnosis when compared to patients with CAD who tend to have an acute presentation of MI leading to PCI.
Our study also showed that certain subgroups of the patients with PAD and CeVD were at higher risk of having adverse events. Among these groups CVA with hemiparesis had the highest associated risk of MACCE. All categories of CVA were also associated with higher risk of repeat stroke at 1 year which aligns with findings of Song C et al. where patients with prior stroke or TIA had higher risk of in-hospital stroke, 90-day readmission and long-term mortality (12). Based the findings of various prior studies it has been established that both PAD and CeVD are independent risk factors for predicting the outcomes of MACCE after PCI [12], [15], [16], [17]. Our study found that patients with prior intervention among the PAD group and patients who had CVA with hemiparesis among the CeVD group were associated with the highest risk of MACCE at one year. This points towards the trend of worsening outcomes with increasing disease severity of PAD and CeVD.
Bleeding was found to be significantly higher only in PAD patients. Prior studies state that patients with history of PAD have an increased risk of bleeding post PCI [30], [31]. We also observed that a higher number of patients in PAD, CeVD and polyvascular groups were discharged on anticoagulant medication and clopidogrel along with the standard antiplatelet therapy, this may explain the rise in bleeding events. When looking into specific subgroups statistical significance was only achieved in association between all bleeding and PAD with prior intervention. The CASPAR trial showed significantly higher total bleeding events in patients who underwent bypass surgery when patients were given clopidogrel along with aspirin compared to aspirin monotherapy (32). The VOYAGER trial which investigated the addition of rivaroxaban to aspirin therapy in PAD patients undergoing revascularization had a significant increase in ISTH major bleeding when compared to aspirin monotherapy (33). Although statistical significance was not achieved the COMPASS trial found higher rates of fatal and symptomatic bleeding when patients were given rivaroxaban and aspirin together compared to aspirin monotherapy in patients with chronic vascular disease (34). Although the VOYAGER and COMPASS trials showed higher rates of bleeding they conclude a significant benefit in reducing adverse outcomes with the addition of anticoagulation therapy to aspirin [33], [34]. Our study concludes that the risk of bleeding continues to be a concern in high risk populations like PAD with prior vascular bypass or PTA which warrants care while incorporating an anticoagulant medication into the post PCI treatment regimen. In the present study we found that CeVD was not associated with bleeding. Prior studies also concluded that patients with history of prior stroke did not have a higher risk for bleeding after PCI [35], [36], [37].
5. CLINICAL IMPLICATIONS
Based on our findings we see that the presence of PAD, CeVD or both is associated with a higher burden of comorbidities and an increased risk of MACCE. Specific subcategories of PAD and CeVD such as PAD with history of bypass or PTA and CVA with hemiparesis should be targeted for close monitoring and follow-up post-PCI. Pre-procedural planning should include stratification for subgroup specific risk. The use of bleeding risk scores such as PRECISE-DAPT may help predict risk of bleeding in these high-risk populations. Consideration for shorter duration of DAPT and obtaining radial access for procedure may reduce the risk of bleeding in patients who are burdened with PAD. A multidisciplinary approach to follow-up post PCI may help prevent recurrence of repeat stroke in patients with CeVD. We believe further clinical trials are warranted to understand the impact of the various presentation subgroups in a broader geographic setting to help create subgroup specific protocols (intensity, duration of antiplatelets and anticoagulants) for post PCI treatment.
6. STUDY LIMITATIONS
This study has several limitations, first being that the study design was an observational retrospective study which can pose selection and referral bias. This study selected patients in 10 years between 2012–2022 during which several advancements have been made in the available technology and techniques used in coronary interventions which could lead to disparity in the event rates when considered in retrospect along the observed study duration. All patients included in this study were from a single tertiary academic center in New York which limits the generalizability of the reported conclusions. Our lab has also continued to use a femoral dominant approach to our PCIs throughout the years despite other centers shifting towards a primarily Radial approach, we report very low numbers of access site bleed but this may still affect generalizability of our bleeding events. We did not include the patients in the polyvascular group for subgroup analysis due to small patient population. PAD and CeVD subcategories were generalized based on the presentation recorded in the electronic medical records. Confirmatory imaging was not a universal requirement for diagnosis of PAD which may lead to some inaccuracy of diagnosis but reflects real world practice. Degree of claudication was not taken into consideration in our analysis which can cause an underrepresentation of risk of MACCE in higher claudication classes. Some key subgroups such as PAD with prior (amputation, aortic aneurysm) and CeVD with prior (carotid stenting, carotid endarterectomy) had insufficient patient population to asses association with MACCE and were not included in the subgroup analysis. Despite extensive multivariate adjustment it is still possible that some unmeasured confounders may have also influenced the results of this study.
7. CONCLUSION
PAD,CeVD and polyvascular disease demonstrate a higher risk of MACCE in patients undergoing PCI. This increased risk of MACCE appears to be driven by those with prior intervention or CVA with hemiparesis. An increased risk of bleeding is seen in patients with PAD, polyvascular disease and PAD with prior intervention when stratified by subgroup.
CRediT authorship contribution statement
Pavan Gadhe: Writing – review & editing, Writing – original draft, Conceptualization. Raman Sharma: Writing – review & editing, Writing – original draft, Supervision, Conceptualization. Serdar Farhan: Writing – review & editing, Supervision, Conceptualization. David Song: Writing – review & editing. Vishal Kapur: Writing – review & editing. Arthur Tarricone: Writing – review & editing. Samantha Sartori: Validation, Project administration, Methodology, Formal analysis, Data curation. Angelo Oliva: Formal analysis, Data curation. Yihan Feng: Formal analysis, Data curation. Prakash Krishnan: Writing – review & editing, Conceptualization. Annapoorna Kini: Writing – review & editing. Roxana Mehran: Writing – review & editing, Conceptualization. Samin Sharma: Writing – review & editing, Writing – original draft, Supervision, Conceptualization.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Mehran reports institutional research payments from: Abbott, Alleviant Medical, Chiesi, Concept Medical, Cordis, CPC Clinical Research, Daiichi Sankyo, Duke, Faraday Pharmaceuticals, Idorsia Pharmaceuticals, Janssen, MedAlliance, Medtronic, NewAmsterdam Pharma, Novartis, Novo Nordisk Inc., Population Health Research Institute (PHRI), Protembis GmbH, Radcliffe, RM Global Bioaccess Fund Management, Sanofi US Services, Inc.; Personal fees from: None; Equity < 1% in: Stel, ControlRad (spouse); No Fees from: SCAI (Women in Innovations Committee Member), Faculty Cardiovascular Research Foundation (CRF), Women as One (Founding Director); Honorarium: AMA − JAMA Cardiology (Associate Editor),ACC (Vice President, BOT Member, SC Member CTR Program). All other authors state that they have no relevant disclosures for the current manuscript.
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