Abstract
Background
Little is known about the use of cangrelor in patients with acute myocardial infarction (AMI) undergoing coronary artery bypass grafting (CABG).
Objectives
The purpose of this study was to examine characteristics and patterns of cangrelor utilization of CABG patients in CAMEO (Cangrelor in Acute Myocardial Infarction: Effectiveness and Outcomes), a multicenter registry of AMI patients receiving cangrelor and/or oral P2Y12 inhibitors.
Methods
We examined characteristics and patterns of cangrelor utilization in AMI patients who underwent CABG. Patients receiving cangrelor post-CABG were excluded. “Bridge” dosing was defined as cangrelor ≤1 μg/kg/min and percutaneous coronary intervention (PCI) dosing (>1 and ≤ 4 μg/kg/min).
Results
In CAMEO, 246 patients underwent CABG (42.3% received cangrelor). Of these, 30.9% received cangrelor only, 11.4% received an oral P2Y12 inhibitor and cangrelor, 8.9% received an oral P2Y12 inhibitor followed by cangrelor, 21.1% received an oral P2Y12 inhibitor only, and 36.6% received neither. The median age was 63 vs 66 years in cangrelor- vs non-cangrelor-treated patients. Patients treated with cangrelor were more likely to have PCI during hospitalization (P < 0.001) and less likely to have radial access (P = 0.005). Time from admission to CABG and overall length of stay was shorter for cangrelor- vs non-cangrelor-treated patients (median 3.8 vs 5.1 days; 10.5 vs 12.7 days). Among cangrelor-treated CABG patients, 26% received the “bridge” dose, 64% received the PCI dose, and 10% received a combination of both.
Conclusions
Cangrelor use in patients with AMI undergoing CABG varies, with over 25% of cangrelor-treated patients receiving “bridge” dosing prior to CABG. Timing from hospital admission to CABG and overall length of stay were significantly shorter in cangrelor-treated patients.
Key words: CABG, cangrelor
Central Illustration
Among patients presenting with an acute myocardial infarction (MI), roughly 7% to 9% will undergo coronary artery bypass grafting (CABG) during the index admission.1 Some patients may receive an oral P2Y12 inhibitor as an acute treatment prior to angiography which requires a “washout” period if undergoing CABG due to the risk of bleeding in the perisurgical time period. Other patients may have an acute ST-segment elevation MI (STEMI) requiring emergent revascularization of the culprit lesion but have residual disease best treated by CABG. For these patients and patients with high-risk multivessel disease, cangrelor, an intravenous direct-acting P2Y12 receptor inhibitor, may be considered optimal to serve as an antiplatelet agent that can be turned off just prior to CABG. It may also serve as a “bridge” while an oral P2Y12 inhibitor is washing out. Current international practice guidelines recommend that P2Y12 inhibitor therapy should be held for at least 5 days for clopidogrel or ticagrelor and 7 days for prasugrel before surgery due to the risk of bleeding.2,3 Cangrelor may also be used if there is high-risk disease present and an antiplatelet is needed while awaiting a surgical procedure, including CABG.4, 5, 6 The BRIDGE (Maintenance of Platelet Inhibition With Cangrelor After Discontinuation of Thienopyridines in Patients Undergoing Surgery) trial7 demonstrated that the use of cangrelor while washing out an oral P2Y12 inhibitor prior to CABG resulted in a higher rate of maintenance platelet inhibition without a significant increase in major bleeding compared with placebo.
The CAMEO (Cangrelor in Acute Myocardial Infarction: Effectiveness and Outcomes) registry is the largest observational registry of cangrelor use in patients with an acute MI. Data were collected in a subset of patients in the registry treated with cangrelor, including dosage and duration, as well as outcomes, prior to CABG. The registry also enrolled patients who were not treated with cangrelor and underwent CABG. We hypothesized that patients treated with cangrelor prior to undergoing CABG would have a shorter time from admission to CABG and would have more clinical comorbidities compared with patients not treated with cangrelor undergoing CABG.
Methods
The CAMEO registry began enrolling patients in October 2019 and completed enrollment in June 2024 from a total of 12 U.S. centers. Patients were enrolled if they met the following criteria: 1) capability to perform percutaneous coronary intervention (PCI) and CABG; 2) minimum of 10 patients with MI treated monthly; and 3) minimum use of cangrelor in at least 2 patients with MI monthly. Each hospital obtained approval from their local Institutional Review Board before enrolling patients. With anonymous data collection, the registry was conducted under a waiver of consent and Health Insurance Portability and Accountability Act authorization.
Study design and population
Site selection and study design have been previously described.8 In brief, each hospital began participation in phase 1 of the registry by retrospectively collecting data on approximately 50 consecutive patients within the 4 months before site activation. These patients met the following criteria: age ≥18 years; underwent coronary angiography for STEMI or non-STEMI (NSTEMI); and received any P2Y12 inhibitor (cangrelor or oral P2Y12 inhibitor) during the first 48 hours after hospitalization for MI. After completion of phase 1, each hospital proceeded to phase 2, in which data were collected in a 2:1 ratio for patients with MI treated with cangrelor and those not treated with cangrelor. Phase 2 was designed to focus on the evaluation of patients treated with cangrelor while compiling a contemporary control cohort. These patients met the following criteria: age ≥18 years; underwent coronary angiography for STEMI or NSTEMI; and received any P2Y12 inhibitor (cangrelor or oral P2Y12 inhibitor) during the index MI admission and within 7 days prior to CABG. This analysis is on a subset of patients who underwent CABG (Supplemental Figure 1).
Definitions
Major adverse cardiovascular events (MACE) were defined as a composite of in-hospital (and within 7 days postdischarge) recurrent MI, stroke, or death. Bleeding events were defined as any event associated with a hemoglobin drop ≥3 g/dL; any event requiring blood transfusion (platelet or red blood cell); or any bleeding event that required an intervention or surgery to stop bleeding, such as surgical closures, exploration of the arteriotomy site, balloon angioplasty to seal an arterial tear, or endoscopy with cautery of a gastrointestinal bleed.9
We examined the different types of infusions and antiplatelet strategies administered to patients in the registry undergoing CABG. Patients who received cangrelor after undergoing CABG were excluded, as the use of cangrelor in these cases may be for reasons other than an acute MI being treated with CABG. A “bridge” dose was defined as a cangrelor dose ≤1 μg/kg/min.4 The PCI dose of cangrelor was defined as a cangrelor dose >1 but ≤4 μg/kg/min.10 We defined the administration of an upstream oral P2Y12 inhibitor as the start time of the first oral P2Y12 inhibitor prior to CABG.
Statistical analysis
We examined demographic and clinical characteristics of the cangrelor-treated and non-cangrelor-treated patients who underwent CABG after an acute MI, as well as the characteristics of all patients with acute MI in the registry who underwent CABG. Categorical variables are presented as frequency counts and absolute percentages; continuous variables are presented as median (25th, 75th percentiles). For categorical variables, differences were compared using either the chi-squared test or Fisher exact test as appropriate; for continuous variable, differences were compared using the Wilcoxon rank sum test or Student’s t-test as appropriate.
We described the frequency and counts of patients undergoing CABG with various antiplatelet strategies and the frequency of antiplatelet strategies used including only cangrelor, upstream oral P2Y12 inhibitor and cangrelor infusion, oral P2Y12 inhibitor only, and no antiplatelet medication. We also described the frequency and counts of patients receiving a “bridge” dose or PCI dose of cangrelor. We examined the median (25th, 75th) time from hospital admission to CABG in days. We described the flow of clinical events in patients from time of admission to CABG using a Sankey Diagram.
In addition, we described factors predictive of cangrelor use in those undergoing CABG. We examined clinical outcomes, including bleeding and MACE, among patients undergoing CABG who were treated with cangrelor vs those not treated with cangrelor. To examine the association between clinical characteristics and cangrelor use, a logistic regression model for the outcome of cangrelor use as a function of the clinical characteristics was fit. For continuous variables, the linearity assumption was assessed and if a nonlinearity relationship was found, an appropriate transformation that adequately accounted for the nonlinearity was applied to the covariate before including in the final association model.
All statistical analyses were performed using SAS v9.4 (SAS Institute) and R v4.3.2 (R Core Team). All tests were 2-sided, with P < 0·05 considered statistically significant.
Results
The final study population included 246 patients undergoing CABG with 104 (42.3%) treated with cangrelor. Of those undergoing CABG, 30.9% received cangrelor only, 11.4% received an oral P2Y12 inhibitor and cangrelor, 21.1% received an oral P2Y12 inhibitor only, and 36.6% received neither an oral P2Y12 inhibitor nor cangrelor before CABG.
Table 1 describes the clinical characteristics of those who underwent CABG and did or did not receive cangrelor. The median age was 63 (58, 71) vs 66 (59, 73) years for the cangrelor-treated vs non-cangrelor-treated group (P = 0.198). Clinical characteristics, such as diabetes, prior MI, and heart failure, were not statistically different between the 2 groups; however, patients treated with cangrelor vs those who were not were significantly less likely to be on dialysis (0% vs 5.6%; P = 0.022). Additionally, cangrelor-treated vs non-cangrelor-treated patients were significantly more likely to have higher admission hemoglobin (median 14.2 g/dL [13.0, 15.5] vs 13.4 g/dL [11.7, 14.6]) and platelet counts (median 241 [199, 293] vs 228 [192, 268] 109/L; P < 0.05 for both). Patients who received cangrelor vs those who did not were also more likely to have a PCI procedure performed during hospitalization (52.9% vs 4.2%; P < 0.001) and were less likely to have undergone radial access during coronary angiography (58.7% vs 75.4%; P = 0.005). All patients treated with cangrelor had PCI performed within 1 hour of the initial angiography.
Table 1.
Clinical Characteristics of Patients Undergoing CABG Stratified by Cangrelor Treatment
| All (N = 246) | Cangrelor (N = 104) | No Cangrelor (N = 142) | P Value | |
|---|---|---|---|---|
| Demographics | ||||
| Age, median (25th, 75th), y | 64.0 (58.0, 72.0) | 62.5 (58.0, 71.0) | 66.0 (59.0, 73.0) | 0.198 |
| Female | 65/246 (26.4%) | 30/104 (28.8%) | 35/142 (24.6%) | 0.461 |
| Race | 0.098 | |||
| Black | 53/246 (21.5%) | 16/104 (15.4%) | 37/142 (26.1%) | |
| East Asian | 2/246 (0.8%) | 1/104 (1.0%) | 1/142 (0.7%) | |
| Multiracial | 1/246 (0.4%) | 1/104 (1.0%) | 0/142 (0.0%) | |
| South Asian | 5/246 (2.0%) | 3/104 (2.9%) | 2/142 (1.4%) | |
| White | 157/246 (63.8%) | 74/104 (71.2%) | 83/142 (58.5%) | |
| Hispanic | 32/246 (13.0%) | 13/104 (12.5%) | 19/142 (13.4%) | 0.839 |
| Private health insurance | 120/246 (48.8%) | 44/104 (42.3%) | 76/142 (53.5%) | 0.082 |
| Clinical history | ||||
| Diabetes | 125/246 (50.8%) | 46/104 (44.2%) | 79/142 (55.6%) | 0.077 |
| Hypertension | 190/246 (77.2%) | 71/104 (68.3%) | 119/142 (83.8%) | 0.004 |
| Dyslipidemia | 176/246 (71.5%) | 70/104 (67.3%) | 106/142 (74.6%) | 0.208 |
| Prior MI | 36/246 (14.6%) | 18/104 (17.3%) | 18/142 (12.7%) | 0.310 |
| Prior PCI | 37/246 (15.0%) | 23/104 (22.1%) | 14/142 (9.9%) | 0.008 |
| Prior CABG | 5/246 (2.0%) | 3/104 (2.9%) | 2/142 (1.4%) | 0.653 |
| Prior HF | 25/246 (10.2%) | 8/104 (7.7%) | 17/142 (12.0%) | 0.272 |
| PAD | 22/246 (8.9%) | 6/104 (5.8%) | 16/142 (11.3%) | 0.135 |
| Stroke/TIA | 21/246 (8.5%) | 9/104 (8.7%) | 12/142 (8.5%) | 0.955 |
| Atrial fibrillation/flutter | 16/246 (6.5%) | 7/104 (6.7%) | 9/142 (6.3%) | 0.902 |
| Dialysis | 8/246 (3.3%) | 0/104 (0.0%) | 8/142 (5.6%) | 0.022 |
| Current/recent smoker | 85/246 (34.6%) | 35/104 (33.7%) | 50/142 (35.2%) | 0.800 |
| Chronic lung disease | 18/246 (7.3%) | 11/104 (10.6%) | 7/142 (4.9%) | 0.093 |
| Medications in the 24 h prior to admission | ||||
| P2Y12 inhibitors overall | 40/246 (16.3%) | 17/104 (16.3%) | 23/142 (16.2%) | 0.975 |
| Clopidogrel | 30/246 (12.2%) | 12/104 (11.5%) | 18/142 (12.7%) | 0.788 |
| Prasugrel | 0/246 (0.0%) | 0/104 (0.0%) | 0/142 (0.0%) | |
| Ticagrelor | 10/246 (4.1%) | 5/104 (4.8%) | 5/142 (3.5%) | 0.747 |
| Oral anticoagulant | 24/246 (9.8%) | 10/104 (9.6%) | 14/142 (9.9%) | 0.949 |
| Presenting features | ||||
| Killip class IV | 10/246 (4.1%) | 6/104 (5.8%) | 4/142 (2.8%) | 0.330 |
| Admission creatinine, median (25th, 75th), mg/dL | 1.0 (0.8, 1.2) | 1.0 (0.9, 1.2) | 1.0 (0.8, 1.2) | 0.735 |
| Admission hemoglobin, median (25th, 75th), g/dL | 13.8 (12.2, 14.9) | 14.2 (13.0, 15.5) | 13.4 (11.7, 14.6) | <0.001 |
| Admission platelets, median (25th, 75th), 109/L | 235.0 (193.0, 275.0) | 241.0 (199.0, 293.0) | 228.0 (192.0, 268.0) | 0.034 |
| LVEF <40% | 69/244 (28.3%) | 30/103 (29.1%) | 39/141 (27.7%) | 0.802 |
| Procedural characteristics | ||||
| PCI procedure performed | 61/246 (24.8%) | 55/104 (52.9%) | 6/142 (4.2%) | <0.001 |
| Symptoms and signs at the time of PCI | ||||
| Emesis | 0/61 (0.0%) | 0/55 (0.0%) | 0/6 (0.0%) | |
| Active chest discomfort | 14/61 (23.0%) | 12/55 (21.8%) | 2/6 (33.3%) | 0.613 |
| ST elevation | 16/61 (26.2%) | 14/55 (25.5%) | 2/6 (33.3%) | 0.648 |
| Sustained VT/VF | 3/61 (4.9%) | 2/55 (3.6%) | 1/6 (16.7%) | 0.271 |
| None of the above | 34/61 (55.7%) | 31/55 (56.4%) | 3/6 (50.0%) | 1.000 |
| Primary territory treated | ||||
| Left main | 1/61 (1.6%) | 1/55 (1.8%) | 0/6 (0.0%) | 1.000 |
| Proximal LAD | 6/61 (9.8%) | 6/55 (10.9%) | 0/6 (0.0%) | 1.000 |
| Mid/distal LAD | 4/61 (6.6%) | 3/55 (5.5%) | 1/6 (16.7%) | 0.346 |
| Diagonal branch | 0/61 (0.0%) | 0/55 (0.0%) | 0/6 (0.0%) | |
| RCA | 25/61 (41.0%) | 23/55 (41.8%) | 2/6 (33.3%) | 1.000 |
| RPDA RPL AM branch | 3/61 (4.9%) | 3/55 (5.5%) | 0/6 (0.0%) | 1.000 |
| Circumflex | 15/61 (24.6%) | 13/55 (23.6%) | 2/6 (33.3%) | 0.630 |
| OM LPDA LPL branch ramus | 9/61 (14.8%) | 7/55 (12.7%) | 2/6 (33.3%) | 0.212 |
| Thrombus visualized | 1.000 | |||
| No | 28/57 (49.1%) | 25/51 (49.0%) | 3/6 (50.0%) | |
| Yes—native vessel | 29/57 (50.9%) | 26/51 (51.0%) | 3/6 (50.0%) | |
| Postprocedure % stenosis <25% | 37/60 (61.7%) | 35/54 (64.8%) | 2/6 (33.3%) | 0.191 |
| Postprocedure TIMI flow | 0.209 | |||
| 0 | 6/59 (10.2%) | 4/54 (7.4%) | 2/5 (40.0%) | |
| 1 | 1/59 (1.7%) | 1/54 (1.9%) | 0/5 (0.0%) | |
| 2 | 2/59 (3.4%) | 2/54 (3.7%) | 0/5 (0.0%) | |
| 3 | 50/59 (84.7%) | 47/54 (87.0%) | 3/5 (60.0%) | |
| Multivessel PCI | 5/61 (8.2%) | 5/55 (9.1%) | 0/6 (0.0%) | 1.000 |
| Stent(s) used | ||||
| Drug-eluting stent ramus | 30/61 (49.2%) | 28/55 (50.9%) | 2/6 (33.3%) | 0.671 |
| Bare metal | 1/61 (1.6%) | 1/55 (1.8%) | 0/6 (0.0%) | 1.000 |
| Bioabsorbable | 4/61 (6.6%) | 4/55 (7.3%) | 0/6 (0.0%) | 1.000 |
| None | 30/61 (49.2%) | 26/55 (47.3%) | 4/6 (66.7%) | 0.425 |
| Number of stents, median (25th, 75th) | 1.0 (1.0, 2.0) | 1.0 (1.0, 2.0) | 1.0 (1.0, 1.0) | 0.431 |
| Smallest stent diameter, mm, median (25th, 75th) | 3.0 (2.8, 3.5) | 3.0 (2.8, 3.5) | 3.5 (3.0, 4.0) | 0.451 |
| Thrombectomy | 7/61 (11.5%) | 6/55 (10.9%) | 1/6 (16.7%) | 0.535 |
| MCS used | ||||
| No | 31/61 (50.8%) | 28/55 (50.9%) | 3/6 (50.0%) | 1.000 |
| IABP | 29/61 (47.5%) | 26/55 (47.3%) | 3/6 (50.0%) | 1.000 |
| Impella | 2/61 (3.3%) | 2/55 (3.6%) | 0/6 (0.0%) | 1.000 |
| Tandem/Heart | 0/61 (0.0%) | 0/55 (0.0%) | 0/6 (0.0%) | |
| LVAD | 0/61 (0.0%) | 0/55 (0.0%) | 0/6 (0.0%) | |
| ECMO | 1/61 (1.6%) | 1/55 (1.8%) | 0/6 (0.0%) | 1.000 |
| Duration of MCS after cath | 0.345 | |||
| <24 h | 8/30 (26.7%) | 6/27 (22.2%) | 2/3 (66.7%) | |
| 1–2 d | 7/30 (23.3%) | 6/27 (22.2%) | 1/3 (33.3%) | |
| 3–5 d | 9/30 (30.0%) | 9/27 (33.3%) | 0/3 (0.0%) | |
| >5 d | 6/30 (20.0%) | 6/27 (22.2%) | 0/3 (0.0%) | |
| Arterial access site | 0.005 | |||
| Femoral | 76/246 (30.9%) | 41/104 (39.4%) | 35/142 (24.6%) | |
| Radial | 168/246 (68.3%) | 61/104 (58.7%) | 107/142 (75.4%) | |
| Other | 2/246 (0.8%) | 2/104 (1.9%) | 0/142 (0.0%) | |
| Arterial closure device used | 116/246 (47.2%) | 46/104 (44.2%) | 70/142 (49.3%) | 0.432 |
Values are n/N (%), unless otherwise indicated.
AM = acute marginal; CABG = coronary artery bypass grafting; ECMO = extracorporeal membrane oxygenation; HF = heart failure; IABP = intraaortic balloon pump; LAD = left anterior descending; LPDA = left posterior descending artery; LPL = left posterolateral; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MCS = mechanical circulatory support; MI = myocardial infarction; OM = obtuse marginal; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; RCA = right coronary artery; RPDA = right posterior descending artery; RPL = right posterolateral; TIA = transient ischemic attack; VF = ventricular fibrillation; VT = ventricular tachycardia.
Time from admission to CABG was shorter for patients treated with cangrelor than those who did not receive cangrelor (median 3.8 days [2.4, 5.9] vs 5.1 days [3.5, 7.7]; P = 0.003). The overall length of stay was significantly shorter for patients treated with cangrelor compared with those not receiving cangrelor (median 10.5 days [7.9, 15.0] vs 12.7 days [10.1, 17.8]; P = 0.003). The timing from admission to CABG is further stratified by antiplatelet strategy in Table 2. Patients treated with only cangrelor were taken for CABG fastest (median 3.3 days [1.8, 5.2]) compared to patients who received no antiplatelet therapy (median 4.3 [2.8, 7.2]). The median time from admission to CABG for patients treated with an oral P2Y12 inhibitor was approximately 6 days, regardless of cangrelor treatment (Table 2). Among cangrelor-treated patients undergoing CABG, 26% received the bridge dose, 64% received the PCI dose, and 10% received a combination of bridge and PCI infusion doses prior to CABG (Central Illustration). Table 3 describes the type of cangrelor dose and duration of infusion.
Table 2.
Timing From Admission to CABG Stratified by Antiplatelet Strategy
| All CABG (N = 246) | Upstream Oral P2Y12 + Cangrelor (n = 28) | Cangrelor Only (n = 76) |
Upstream Oral P2Y12 Only (n = 52) | No Upstream Oral P2Y12 or Cangrelor (n = 90) |
|
|---|---|---|---|---|---|
| Time from admission to CABG, d | |||||
| n | 246 | 28 | 76 | 52 | 90 |
| Mean (SD) | 5.2 (3.6) | 7.0 (4.3) | 3.9 (3.4) | 6.6 (3.1) | 5.1 (3.3) |
| Median (25th, 75th) | 4.7 (2.9, 6.8) | 5.9 (3.8, 8.6) | 3.3 (1.8, 5.2) | 6.0 (4.7, 8.7) | 4.3 (2.8, 7.2) |
| Min, max | 0.1, 22.6 | 0.4, 20.9 | 0.1, 22.6 | 1.8, 20.7 | 0.2, 15.7 |
| Time from catheterization to CABG, d | |||||
| n | 246 | 28 | 76 | 52 | 90 |
| Mean (SD) | 4.4 (3.3) | 6.5 (4.3) | 3.5 (3.2) | 5.0 (2.5) | 4.2 (3.1) |
| Median (25th, 75th) | 3.9 (2.2, 5.8) | 5.5 (3.5, 8.4) | 3.0 (1.0, 4.8) | 4.4 (3.4, 6.1) | 3.8 (1.7, 6.0) |
| Min, max | 0.0, 19.8 | 0.3, 19.8 | 0.1, 19.2 | 1.3, 15.8 | 0.0, 14.9 |
Abbreviation as in Table 1.
Central Illustration.
Cangrelor Use in Patients Undergoing CABG
Cangrelor use in patients undergoing CABG was associated with shorter length of stay and shorter wait time to CABG. Over 25% of patients in the analysis awaiting CABG were treated with the “bridge” dose of cangrelor. Abbreviation as in Figure 1.
Table 3.
Cangrelor Dosing and Duration of Infusion Prior to CABG
| N | Infusion Duration (Days) |
|||
|---|---|---|---|---|
| Median (25th, 75th) | Mean (SD) | Min, Max | ||
| All cangrelor-treated patients | 104 | 1.9 (0.5, 4.5) | 2.9 (3.2) | 0.0, 15.8 |
| Only bridge dose | 27 (26%) | 2.3 (1.4, 4.5) | 4.0 (3.7) | 0.4, 15.8 |
| Only PCI dose | 67 (64%) | 1.3 (0.1, 4.1) | 2.2 (2.5) | 0.0, 11.9 |
| Both bridge and PCI dose | 10 (10%) | 3.8 (2.0, 7.3) | 4.8 (4.0) | 0.0, 12.3 |
Abbreviations as in Table 1.
The flow of clinical events from admission until CABG is presented in a Sankey diagram (Figure 1). Table 4 describes the order of clinical events (ie, coronary angiography, CABG, cangrelor treatment) and the frequency with which they occurred. In general, the majority of patients proceeded from coronary angiography to CABG without cangrelor or oral P2Y12 inhibitor (35.4%), and 18.3% received an oral P2Y12 inhibitor before coronary angiography and then underwent CABG. The 2 most common scenarios for patients treated with cangrelor before CABG included coronary angiography followed by cangrelor treatment before CABG (13.0%); and coronary angiography with PCI performed, followed by cangrelor treatment before CABG (12.2%).
Figure 1.
Sankey Diagram Examining Patterns of Antiplatelet Strategies Prior to CABG
The Sankey diagram demonstrates the movement of patients from precardiac catheterization to undergoing CABG, demonstrating what the most common patterns of antiplatelet utilization were prior to CABG. CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.
Table 4.
Order of Clinical Events Prior to CABG and Associated Frequencies of Occurrence
| Order of Events | Frequency Count (N = 246) | Percent of Total Frequency |
|---|---|---|
| Cath, CABG | 87 | 35.4 |
| Oral P2Y12 inhibitor, cath, CABG | 45 | 18.3 |
| Cath, cangrelor, CABG | 32 | 13.0 |
| Cath, PCI, cangrelor, CABG | 30 | 12.2 |
| Oral P2Y12 inhibitor, cath, PCI, cangrelor, CABG | 9 | 3.7 |
| Cangrelor, cath, CABG | 8 | 3.3 |
| Oral P2Y12 inhibitor, cath, cangrelor, CABG | 8 | 3.3 |
| Cath, oral P2Y12 inhibitor, CABG | 5 | 2.0 |
| Cath, PCI, cangrelor, oral, CABG | 5 | 2.0 |
| Cath, PCI, oral P2Y12 inhibitor, cangrelor, CABG | 5 | 2.0 |
| Cath, cangrelor, PCI, CABG | 4 | 1.6 |
| Cath, PCI, CABG | 3 | 1.2 |
| Cangrelor, cath, PCI, CABG | 2 | 0.8 |
| Cangrelor, cath, oral, CABG | 1 | 0.4 |
| Cath, PCI, oral, CABG | 1 | 0.4 |
| Oral P2Y12 inhibitor, cath, PCI, CABG | 1 | 0.4 |
Cath = catheterization; other abbreviations as in Table 1.
Importantly, there were significant differences in practice based on the site where patients received treatment. Table 5 examines the antiplatelet strategies for CABG-treated patients by site. Several sites used cangrelor in the majority of patients undergoing CABG, while other sites used cangrelor infrequently.
Table 5.
Antiplatelet Strategies Prior to CABG Stratified by Site
| Site | All CABG (N = 246) | Upstream Oral + Cangrelor (n = 28) | Cangrelor Only (n = 76) | Upstream Oral P2Y12 Only (n = 52) | No Upstream Oral P2Y12 or Cangrelor (n = 90) |
|---|---|---|---|---|---|
| 1 | 59 | 1/59 (1.7%) | 20/59 (33.9%) | 4/59 (6.8%) | 34/59 (57.6%) |
| 2 | 9 | 1/9 (11.1%) | 1/9 (11.1%) | 5/9 (55.6%) | 2/9 (22.2%) |
| 3 | 15 | 4/15 (26.7%) | 3/15 (20.0%) | 4/15 (26.7%) | 4/15 (26.7%) |
| 4 | 35 | 6/35 (17.1%) | 26/35 (74.3%) | 2/35 (5.7%) | 1/35 (2.9%) |
| 5 | 47 | 2/47 (4.3%) | 4/47 (8.5%) | 10/47 (21.3%) | 31/47 (66.0%) |
| 6 | 7 | 2/7 (28.6%) | 0 | 3/7 (42.9%) | 2/7 (28.6%) |
| 7 | 2 | 0 | 0 | 2/2 (100.0%) | 0 |
| 8 | 13 | 4/13 (30.8%) | 2/13 (15.4%) | 1/13 (7.7%) | 6/13 (46.2%) |
| 9 | 11 | 1/11 (9.1%) | 8/11 (72.7%) | 0 | 2/11 (18.2%) |
| 10 | 25 | 5/25 (20.0%) | 11/25 (44.0%) | 7/25 (28.0%) | 2/25 (8.0%) |
| 11 | 10 | 1/10 (10.0%) | 0 | 3/10 (30.0%) | 6/10 (60.0%) |
| 12 | 13 | 1/13 (7.7%) | 1/13 (7.7%) | 11/13 (84.6%) | 0 |
Abbreviation as in Table 1.
Female sex, a history of prior PCI, admission hemoglobin, and the use of mechanical circulatory support were positively associated with a higher likelihood of using cangrelor in the CABG population (Figure 2). Rates of MACE were highest among those treated with upstream oral antiplatelet therapy and cangrelor (17.9%), followed by only oral P2Y12 inhibitor therapy (11.5%), no antiplatelet therapy (3.3%), and only cangrelor use (2.6%). Rates of bleeding followed a similar pattern with 28.6% of bleeding events occurring in those treated with both oral antiplatelet therapy and cangrelor, followed by only oral antiplatelet therapy (25%), cangrelor only (17.1%), and no antiplatelet therapy (5.6%).
Figure 2.
Factors Predictive of Cangrelor Use in Patients Undergoing CABG
A forest plot of ORs (95% CI) demonstrating factors predictive of cangrelor use in a population of patients with AMI undergoing CABG. Female sex, prior PCI, and admission hemoglobin were predictive of cangrelor use in this population. AMI = acute myocardial infarction; MCS = mechanical circulatory support; other abbreviations as in Figure 1.
Discussion
In the largest observational data set of cangrelor use in patients with acute MI undergoing CABG, we demonstrated that there was significant variability in how cangrelor was dosed and administered. Patients undergoing CABG in the United States had varying strategies of antiplatelet therapies prior to CABG—from no antiplatelet therapies to a combination of intravenous and oral antiplatelets, to various doses (PCI dosing vs “bridge” dosing). The use of cangrelor alone prior to CABG was associated with a significant reduction in time from admission to the patient undergoing CABG. A history of prior PCI, admission hemoglobin, female sex, and the use of mechanical circulatory support were prominent factors predictive of using cangrelor prior to CABG. Importantly, there was significant variation across sites as to the patterns of antiplatelet therapies administered prior to CABG.
A primary driver of cangrelor use prior to CABG is the benefit of having a short-acting antiplatelet therapy administered that: 1) allows for antiplatelet therapy while washing out an oral P2Y12 inhibitor; and 2) maintains platelet inhibition in patients with high-risk disease while awaiting CABG.11 Indeed, there was a significant reduction in median time from coronary angiography to CABG of over 1 hospitalized day in patients treated with cangrelor. The median time from admission or catheterization to CABG was >5.9 days when the patient got an upstream oral P2Y12 inhibitor, as expected, to allow for washout. Additionally, we showed nearly a 2-day reduction in overall length of stay for patients undergoing CABG when treated with cangrelor. These observations have important implications as an often-cited reason for not utilizing cangrelor is based on cost of the drug. However, as we demonstrated, its use is associated with a significant reduction in hospital length of stay, potentially reducing costs for both payers and health systems. For example, in patients with an acute coronary syndrome going for early angiography, using cangrelor if PCI is warranted in favor of preloading an oral P2Y12 inhibitor may reduce time to CABG. In patients with acute coronary syndrome, primarily NSTEMI, the wait for angiography may not be within hours of presentation and may necessitate oral preloading with subsequent washout if CABG is indicated. TARGET-CABG (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG),12 which enrolled patients undergoing nonemergent CABG to clopidogrel with thromboelastography testing (to determine tensile strength of the fibrin-platelet clot) vs no upstream clopidogrel, found no significant difference in bleeding or chest tube drainage between the 2 groups. Depending on thromboelastography thresholds, wait time for CABG was potentially as short as 1 day after treatment with clopidogrel. In another larger trial of standard of care, P2Y12 receptor inhibitor withdrawn 5 to 7 days before CABG, vs the intervention group, daily measurements of platelet reactivity, a strategy based on platelet reactivity guidance was noninferior and associated with a shortened wait time to CABG and decreased hospital expenses.13 This study, along with others examining platelet function testing prior to CABG,14,15 demonstrate an eagerness to shorten inpatient wait times for CABG from a health system, economic, and patient perspective.
Importantly, we examined the practice patterns around use of cangrelor prior to CABG. Our data from multiple high-volume CABG and PCI centers around the country demonstrated that there is wide variation in how patients are treated with antiplatelet therapies before CABG. There was wide variation around whether patients who received an oral P2Y12 inhibitor were then administered cangrelor, administered cangrelor alone without a P2Y12 inhibitor, or received neither. Among those who received cangrelor, over 25% were administered the “bridge” dose, while nearly 66% received the PCI dose. The “bridge” dose is an off-label use of cangrelor that was tested in the BRIDGE trial where the 0.75 μg/kg/min dose was found to significantly maintain platelet inhibition without increased risk of CABG-related bleeding when compared with placebo.4 Interestingly, a recently published single-center study16 examined an institutional strategy of cangrelor “bridge” dosing according to platelet function testing with a goal to maintain a P2Y12 reaction unit (PRU) between 85 and 208 prior to surgical procedures instead of just administering the standard 0.75 μg/kg/min “bridge” dose. The median cangrelor dose to maintain this PRU goal was 0.5 μg/kg/min, and importantly, there were no episodes of stent thrombosis but a median drug cost savings/patient of $1,605.60 ($0, $4,281.56). More information is needed to determine whether this strategy, or other similar strategies, is safe and efficacious.
Study Limitations
There are several limitations to the current study. Primarily, though the registry captures many elements regarding the anatomic features and findings of the coronary angiogram, antiplatelet strategies, and procedural timing, it does not capture the providers’ or operators’ reasoning for administering certain antiplatelet strategies by patient. As with any adjusted analyses with observational data, residual confounding may exist. Our registry includes data from multiple high-volume sites around the country, but those institutions may not represent patterns of antiplatelet use at other hospitals around the country, particularly at hospitals where cangrelor is not on formulary. This may limit the generalizability of the cangrelor experience described in this manuscript compared with other hospitals in the United States. Additionally, the analysis is hypothesis generating and examines the MACE and bleeding outcomes descriptively. Given the limited sample size, an adjusted analysis examining the differences in outcomes between various antiplatelet strategies was not possible, and thus may limit the examination of differences between the outcomes. There may be a relationship between oral P2Y12 inhibitor, cangrelor, and bleeding outcomes post-CABG. However, we do not have the detailed description of each admission and did not adjudicate if the bleeding event related to pharmacologic agents. As a future direction, the evaluation of differences in costs between hospitals based on utilization patterns would further delineate which patterns of use are optimal.
Conclusions
The use of cangrelor in patients undergoing CABG varies with nearly one-third of cangrelor-treated patients receiving “bridge” dosing prior to CABG. Timing from hospital admission to CABG and overall length of stay were significantly shorter in patients who received cangrelor compared with those who did not.
Perspectives.
COMPETENCY IN MEDICAL KNOWLEDGE 1: Cangrelor is an intravenous antiplatelet medication that has a short half-life and may be used as an antiplatelet agent for patients undergoing “washout”p of an oral P2Y12 inhibitor prior to CABG. Because of its short half-life, it can be discontinued just prior to CABG without significant risks of intraoperative bleeding.
COMPETENCY IN MEDICAL KNOWLEDGE 2: Our study demonstrated that there were several characteristics that predicted cangrelor use in acute myocardial infarction patients prior to CABG, including previous PCI, admission hemoglobin, and sex. The use of cangrelor was associated with a significantly shorter time from admission to CABG, and a significantly shorter overall length of stay.
TRANSLATIONAL OUTLOOK: Further work is needed to better understand the utilization of “bridge” dosed cangrelor, and if PRUs can be used to identify the necessary dose of cangrelor for each patient.
Funding support and author disclosures
The CAMEO registry was sponsored by Chiesi USA, Inc, and conducted by Duke Clinical Research Institute, which was responsible for study design and data analysis. Dr Rymer has received research grants from Chiesi, Idorsia, Novo Nordisk, and Abbott. Dr Bhatt has served on the Advisory Boards of Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Tourmaline Bio; has served on the Board of Directors of American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; has served on Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as Site Co-Investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; is a Trustee of the American College of Cardiology; has performed unfunded research for FlowCo. Dr Jones has received research grants to DCRI: Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Merck, NIH, Novartis, and PCORI. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, and Sanofi; also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Bach has received institutional funding for clinical trials from Cytokinetics, BMS, and CSL Behring; has received consulting fees from NGM Biopharmaceuticals, and Novo Nordisk. Dr Waksman has served on Advisory Boards for Abbott Vascular, Boston Scientific, J Valve, Medtronic Inc, Philips IGT, and Pi-Cardia Ltd; has served as a consultant for Abbott Vascular, Biotronik, Boston Scientific, CardioMed LLC, Cordis, Medtronic Inc, Philips IGT, Pi-Cardia Ltd, Swiss Interventional Systems/SIS Medical AG, Transmural Systems Inc, and Venous MedTech; has received institutional grant support from Amgen, Biotronik, Boston Scientific, Chiesi, Medtronic Inc, and Philips IGT; and is an investor in MedAlliance, Pi-Cardia Ltd, and Transmural Systems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For an expanded Methods section and figure, please see the online version of this paper.
Supplemental material
References
- 1.Patlolla S.H., Kanwar A., Cheungpasitporn W., et al. Temporal trends, clinical characteristics, and outcomes of emergent coronary artery bypass grafting for acute myocardial infarction in the United States. J Am Heart Assoc. 2021;10 doi: 10.1161/JAHA.120.020517. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Amsterdam E.A., Wenger N.K., Brindis R.G., et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American college of cardiology/American heart association task force on practice guidelines. Circulation. 2014;130:2354–2394. doi: 10.1161/CIR.0000000000000133. [DOI] [PubMed] [Google Scholar]
- 3.Ferraris V.A., Brown J.R., Despotis G.J., et al. 2011 update to the society of thoracic surgeons and the society of cardiovascular anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–982. doi: 10.1016/j.athoracsur.2010.11.078. [DOI] [PubMed] [Google Scholar]
- 4.Thompson A., Fleischmann K.E., Smilowitz N.R., et al. AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM guideline for perioperative cardiovascular management for noncardiac surgery: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2024;84:1869–1969. doi: 10.1016/j.jacc.2024.06.013. [DOI] [PubMed] [Google Scholar]
- 5.Rossini R., Tarantini G., Musumeci G., et al. A multidisciplinary approach on the perioperative antithrombotic management of patients with coronary stents undergoing surgery: surgery after stenting 2. JACC Cardiovasc Interv. 2018;11:417–434. doi: 10.1016/j.jcin.2017.10.051. [DOI] [PubMed] [Google Scholar]
- 6.Sullivan A.E., Nanna M.G., Wang T.Y., et al. Bridging antiplatelet therapy after percutaneous coronary intervention: JACC review topic of the week. J Am Coll Cardiol. 2021;78:1550–1563. doi: 10.1016/j.jacc.2021.08.013. [DOI] [PubMed] [Google Scholar]
- 7.Angiolillo D.J., Firstenberg M.S., Price M.J., et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307:265–274. doi: 10.1001/jama.2011.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rymer J.A., Bhatt D.L., Angiolillo D.J., et al. Cangrelor use patterns and transition to oral P2Y12 inhibitors among patients with myocardial infarction: initial results from the CAMEO registry. J Am Heart Assoc. 2022;11 doi: 10.1161/JAHA.121.024513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Desai N.R., Kennedy K.F., Cohen D.J., et al. Contemporary risk model for in hospital major bleeding for patients with acute myocardial infarction: the acute coronary treatment and intervention outcomes network (ACTION) Registry®-get with the guidelines (GWTG)®. Am Heart J. 2017;194:16–24. doi: 10.1016/j.ahj.2017.08.004. [DOI] [PubMed] [Google Scholar]
- 10.FDA labeling for cangrelor. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204958Orig1s000Lbl.pdf
- 11.Franchi F., Rollini F., Muñiz-Lozano A., Cho J.R., Angiolillo D.J. Cangrelor: a review on pharmacology and clinical trial development. Expert Rev Cardiovasc Ther. 2013;11:1279–1291. doi: 10.1586/14779072.2013.837701. [DOI] [PubMed] [Google Scholar]
- 12.Mahla E., Suarez T.A., Bliden K.P., et al. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv. 2012;5:261–269. doi: 10.1161/CIRCINTERVENTIONS.111.967208. [DOI] [PubMed] [Google Scholar]
- 13.Nakashima C.A.K., Dallan L.A.O., Lisboa L.A.F., et al. Platelet reactivity in patients with acute coronary syndromes awaiting surgical revascularization. J Am Coll Cardiol. 2021;77:1277–1286. doi: 10.1016/j.jacc.2021.01.015. [DOI] [PubMed] [Google Scholar]
- 14.Mahla E., Tantry U.S., Prüller F., Gurbel P.A. Is there a role for preoperative platelet function testing in patients undergoing cardiac surgery during antiplatelet therapy? Circulation. 2018;138:2145–2159. doi: 10.1161/CIRCULATIONAHA.118.035160. [DOI] [PubMed] [Google Scholar]
- 15.Angiolillo D.J., Galli M., Alexopoulos D., et al. International consensus statement on platelet function and genetic testing in percutaneous coronary intervention: 2024 update. JACC Cardiovasc Interv. 2024;17:2639–2663. doi: 10.1016/j.jcin.2024.08.027. [DOI] [PubMed] [Google Scholar]
- 16.Buck M.M., Barry C.I., Montepara C.A., Verlinden N.J. Platelet function testing to guide cangrelor dosing in patients with temporary mechanical circulatory support or as a bridge to procedure. Clin Appl Thromb Hemost. 2024;30 doi: 10.1177/10760296241237228. [DOI] [PMC free article] [PubMed] [Google Scholar]
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