Abstract
Background/purpose
Dual antiplatelet therapy (DAPT) varies after placement of drug-eluting stents (DES) in patients presenting with acute coronary syndromes (ACS). Our aim was to study patient characteristics and predictors of switching, in-hospital or at discharge, from clopidogrel (CLO) to ticagrelor (TIC) or vice versa.
Methods/materials
The study population included patients with ACS who had DES and initially received either CLO or TIC between January 2011 and December 2017. Patients were divided into 4 groups based on initial DAPT choice and whether DAPT was switched in-hospital or during discharge. Clinical outcomes of interest were bleeding events, need for anticoagulation, and need for in-hospital coronary artery bypass graft (CABG).
Results
We identified 2837 patients who received DES and started on DAPT. DAPT switch from 1 P2Y12 inhibitor to another occurred in 9%, either in-hospital or at discharge. Of 1834 patients started on CLO, 112 were switched to TIC. Of 1003 patients started on TIC, 142 were switched to CLO. The need for in-hospital CABG was 7.8% in the TIC-CLO group compared to none in the CLO-TIC group (p = 0.002). Adjusted for covariates, the TIC-CLO group was 3 times more likely to need anticoagulation with warfarin than the CLO-CLO group (p < 0.001) and over 5 times more likely than the CLO-TIC group and the TIC-TIC group (p < 0.005 for both).
Conclusions
Switching from 1 generation P2Y12 inhibitor to another does occur in ACS patients. Clinical needs such as in-hospital CABG or oral anticoagulation upon discharge are real and dictate the switch from TIC to CLO.
Summary
A single-center observational study of 2837 patients with acute coronary syndromes treated with drug-eluting stents found that some do get switched from one generation P2Y12 inhibitor to another. The switch from clopidogrel to ticagrelor is driven by clinical needs such as in-hospital coronary artery bypass grafting or the need for oral anticoagulation upon discharge.
Highlights
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Switching from 1 generation P2Y12 inhibitor to another does occur in ACS patients.
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Clinical needs are real and dictate the switch from ticagrelor to clopidogrel.
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Switching occurs in approximately 9% of the ACS population treated with DES.
1
Introduction
In patients presenting with acute coronary syndromes (ACS), dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, clopidogrel (CLO), ticagrelor (TIC), or prasugrel is the standard of care following percutaneous coronary intervention (PCI) [ ]. Randomized trials in ACS patients undergoing PCI, prasugrel, or TIC compared to CLO were superior, with lower incidence of major adverse cardiovascular events (MACE), a composite of myocardial infarction (MI), unplanned coronary revascularization, stroke, and death. While prasugrel was associated with reduced rates of ischemic events, there was increased risk of major and fatal bleeding without any significant mortality difference between the 2 groups [ ]. In the PLATO trial, TIC, as compared with CLO, reduced MACE (9.8% vs. 11.7% at 12 months; HR, 0.84; 95% confidence interval, 0.77 to 0.92; p < 0.001), without an increase in the incidence of major bleeding, but with an increase in non-procedure-related bleeding [ ]. TIC, with more rapid onset and consistent platelet inhibition than CLO, is often given as an initial loading dose to achieve early and maximum platelet inhibition prior to coronary cineangiography. Compared with CLO, TIC reduces the incidence of stent thrombosis in ACS patients [ ]. However, due to dyspnea, affordability, bradyarrhythmia, non-coronary artery bypass graft-related major bleeding, or cough, it may be discontinued prematurely [ , ]. We sought to study the patient characteristics, frequency, and in-hospital clinical outcomes associated with switching between the P2Y12 inhibitors.
2
Materials and methods
2.1
Study population
The study population included all patients with ACS who had drug-eluting stents (DES) placed between July 2011 and December 2017. ACS included patients with unstable angina, non-ST-elevation MI, or ST-elevation MI. We excluded patients treated with prasugrel, as it is contraindicated in patients with body weight <60 kg, patients with renal dysfunction, or patients on oral anticoagulation. Prespecified clinical and laboratory data during hospital stays were obtained from hospital charts reviewed by independent research personnel blinded to the objectives of the study. Primary-source documents were obtained for all events and were adjudicated by physicians not involved in the procedures and unaware of the study objectives. All patients provided informed consent for both the procedure and subsequent data collection and analysis for research purposes. The study was approved by the local institutional review board. A dedicated data-coordinating center performed all data management and analyses.
2.2
Procedural details
Vascular access approach, periprocedural anticoagulation, and type of stent selected were at the operator’s discretion. Standard practice was followed for all patients, whether receiving DES or not, for discharge DAPT. All patients received 325 mg of aspirin before the PCI procedure. P2Y12 inhibitor loading before the procedure (300 or 600 mg of CLO, 180 mg of TIC) was given at the operator’s discretion. The periprocedural antithrombotic regimen included unfractionated heparin targeted to achieve an activated clotting time of 200 to 300 s with or without a glycoprotein IIb/IIIa inhibitor, or bivalirudin, was selected at the operator’s discretion. At the end of the procedure, aspirin was prescribed indefinitely, and CLO or TIC was prescribed for a minimum 12 months.
2.3
Study outcomes
The clinical outcomes Q-wave MI, stent thrombosis, cerebrovascular accident, or transient ischemic attack were as defined by the Academic Research Consortium [ ]. In-hospital outcomes included access site hematoma >4 cm, any gastrointestinal bleeding, major bleeding, and vascular complications requiring intervention. Major bleeding was defined as any gastrointestinal bleeding, hematocrit drop >15, or hematoma (>4 cm) with hematocrit >15. Gastrointestinal bleeding includes both evidence of upper (coffee ground emesis, endoscopic demonstration of active bleeding) or lower (melena, hematochezia or endoscopic evidence of an active bleeding site) bleeding. For our study, in-hospital mortality was not a meaningful endpoint and therefore was not evaluated.
2.4
Statistical analysis
Baseline characteristics are presented as mean ± standard deviation for continuous variables and percentages for categorical variables. For variables with missing data, percentages were calculated using the number of patients with data present for that variable. Differences in continuous variables between patients were compared with a Student t -test. Categorical variables were compared with the chi-square test or Fisher exact test when appropriate. The impact of P2Y12 inhibitor switching on the need for anticoagulation at discharge was analyzed by logistic regression. Switching groups were: CLO-CLO, CLO-TIC, TIC-CLO, and TIC-TIC, with CLO-CLO as the reference group. Odds ratios were adjusted for age, sex, race, hypertension, diabetes, prior coronary artery bypass graft (CABG), peripheral vascular disease, acute MI, cardiogenic shock, and left ventricular ejection fraction. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
2
Materials and methods
2.1
Study population
The study population included all patients with ACS who had drug-eluting stents (DES) placed between July 2011 and December 2017. ACS included patients with unstable angina, non-ST-elevation MI, or ST-elevation MI. We excluded patients treated with prasugrel, as it is contraindicated in patients with body weight <60 kg, patients with renal dysfunction, or patients on oral anticoagulation. Prespecified clinical and laboratory data during hospital stays were obtained from hospital charts reviewed by independent research personnel blinded to the objectives of the study. Primary-source documents were obtained for all events and were adjudicated by physicians not involved in the procedures and unaware of the study objectives. All patients provided informed consent for both the procedure and subsequent data collection and analysis for research purposes. The study was approved by the local institutional review board. A dedicated data-coordinating center performed all data management and analyses.
2.2
Procedural details
Vascular access approach, periprocedural anticoagulation, and type of stent selected were at the operator’s discretion. Standard practice was followed for all patients, whether receiving DES or not, for discharge DAPT. All patients received 325 mg of aspirin before the PCI procedure. P2Y12 inhibitor loading before the procedure (300 or 600 mg of CLO, 180 mg of TIC) was given at the operator’s discretion. The periprocedural antithrombotic regimen included unfractionated heparin targeted to achieve an activated clotting time of 200 to 300 s with or without a glycoprotein IIb/IIIa inhibitor, or bivalirudin, was selected at the operator’s discretion. At the end of the procedure, aspirin was prescribed indefinitely, and CLO or TIC was prescribed for a minimum 12 months.
2.3
Study outcomes
The clinical outcomes Q-wave MI, stent thrombosis, cerebrovascular accident, or transient ischemic attack were as defined by the Academic Research Consortium [ ]. In-hospital outcomes included access site hematoma >4 cm, any gastrointestinal bleeding, major bleeding, and vascular complications requiring intervention. Major bleeding was defined as any gastrointestinal bleeding, hematocrit drop >15, or hematoma (>4 cm) with hematocrit >15. Gastrointestinal bleeding includes both evidence of upper (coffee ground emesis, endoscopic demonstration of active bleeding) or lower (melena, hematochezia or endoscopic evidence of an active bleeding site) bleeding. For our study, in-hospital mortality was not a meaningful endpoint and therefore was not evaluated.
2.4
Statistical analysis
Baseline characteristics are presented as mean ± standard deviation for continuous variables and percentages for categorical variables. For variables with missing data, percentages were calculated using the number of patients with data present for that variable. Differences in continuous variables between patients were compared with a Student t -test. Categorical variables were compared with the chi-square test or Fisher exact test when appropriate. The impact of P2Y12 inhibitor switching on the need for anticoagulation at discharge was analyzed by logistic regression. Switching groups were: CLO-CLO, CLO-TIC, TIC-CLO, and TIC-TIC, with CLO-CLO as the reference group. Odds ratios were adjusted for age, sex, race, hypertension, diabetes, prior coronary artery bypass graft (CABG), peripheral vascular disease, acute MI, cardiogenic shock, and left ventricular ejection fraction. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
3
Results
Baseline characteristics are as shown in Table 1 . We identified 2837 patients who were started on loading doses of CLO or TIC and were discharged on the same agent or were switched to TIC or CLO. The study population was divided into 4 groups based on the initial P2Y12 inhibitor received and the P2Y12 inhibitor at discharge: CLO-CLO group (clopidogrel to clopidogrel), CLO-TIC group (clopidogrel to ticagrelor), TIC-CLO group (ticagrelor to clopidogrel), and TIC-TIC group (ticagrelor to ticagrelor). In-hospital switch from 1 P2Y12 inhibitor to another occurred in 9% of the patients. Of 1834 patients who were started on CLO, 112 (6%) were switched to TIC at discharge (CLO-TIC). Of 1003 patients who received TIC, 142 (14%) were switched to CLO at discharge (TIC-CLO). There were no significant differences between the 2 switched groups except prior history of coronary artery disease, which was higher in the CLO-TIC group, and hypertension, which was higher in the TIC-CLO group.
| Variables | (clopidogrel to clopidogrel) CLO-CLO group (n = 1722, 61%) | (clopidogrel to ticagrelor) CLO-TIC group (n = 112, 4%) | (ticagrelor to clopidogrel) TIC-CLO group (n = 142, 5%) | (ticagrelor to ticagrelor) TIC-TIC group (n = 861, 30%) | p-Value for all 4 groups | p-Value (CLO-TIC vs. TIC-CLO groups) |
|---|---|---|---|---|---|---|
| Age – years (Median ± SD) | 66 ± 12 | 60 ± 13 | 64 ± 12 | 62 ± 12 | <0.001 | <0.001 |
| Men | 1093/1722 (63.5%) | 89/112 (80%) | 83/142 (59%) | 573/861 (67%) | 0.001 | 0.001 |
| Race | ||||||
| Black | 732/1722 (42%) | 41/112 (37%) | 52/142 (37%) | 352/861 (41%) | 0.4 | 0.99 |
| White | 857/1722 (50%) | 58/112 (52%) | 67/142 (47%) | 405/861 (47%) | 0.5 | 0.46 |
| Others | 133/1722 (8%) | 13/112 (11%) | 23/142 (16%) | 104/861 (12%) | 0.1 | |
| Diagnosis | ||||||
| Unstable angina pectoris | 346/1722 (20%) | 1/112 (1%) | 4/142 (3%) | 19/861 (2.2%) | <0.001 | 0.27 |
| Acute myocardial infarction | 1376/1722 (80%) | 111/112 (99%) | 138/142 (97%) | 842/861 (98%) | <0.001 | 0.27 |
| Body mass index a | 29.6 ± 6.6 | 29.4 ± 4.6 | 29.4 ± 6.7 | 30.7 ± 6.5 | 0.32 | 0.9 |
| Hypertension | 1468/1720 (85%) | 84/112 (75%) | 120/141 (85%) | 657/861 (76%) | <0.001 | 0.04 |
| Hypercholesterolemia | 1293/1719 (75%) | 71/111 (64%) | 94/141 (67%) | 562/861 (65%) | <0.001 | 0.65 |
| Diabetes Mellitus | 701/1716 (41%) | 35/112 (31%) | 45/141 (32%) | 293/858 (34%) | 0.001 | 0.91 |
| Peripheral vascular disease | 268/1718 (16%) | 11/112 (10%) | 15/141 (11%) | 65/856 (8%) | <0.001 | 0.83 |
| Current smoker | 501/1722 (29%) | 41/112 (37%) | 46/142 (32%) | 291/861 (34%) | 0.04 | 0.48 |
| Prior coronary bypass | 329/1719 (19%) | 9/111 (8%) | 10/141 (7%) | 56/860 (6.5%) | <0.001 | 0.76 |
| Prior history of coronary artery disease | 756/1722 (44%) | 28/112 (25%) | 26/141 (19%) | 198/861 (23%) | <0.001 | <0.001 |
| Left ventricular ejection fraction a | 43 ± 17 (1311) | 44 ± 11 (70) | 43 ± 13 (90) | 45 ± 13 (573) | 0.05 | 0.9 |
| Cardiogenic shock | 41/1721 (2.4%) | 5/111 (4.5%) | 8/142 (6%) | 30/858 (3.5%) | 0.06 | 0.06 |
| End stage renal disease, on Hemodialysis | 117/1721 (7%) | 1/112 (0.9%) | 3/142 (2.1%) | 23/858 (2.7%) | <0.001 | 0.43 |
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