Research Article | Open access
Tom 2023 |Article number 1147352 |https://doi.org/10.1155/2023/1147352
Amit Sachdeva,1Ratnabhushan Mutyala,2Neha Mantri3Shiyun Zhu,4Edward McNulty,3,4i Matthew Solomon4,5
Scientific editor:Thach N. Nguyen
Received8. september 2022
CorrectedFebruary 9, 2023
Accepted3. maj 2023
Released20. maj 2023
Background. Randomized trials have shown superiority of new P2Y12 inhibitors over clopidogrel in patients with acute coronary syndrome (ACS), but the clinical benefits in the community remain controversial. Our objective was to compare the safety and efficacy of clopidogrel with ticagrelor and prasugrel in patients with ACS undergoing percutaneous coronary intervention (PCI) in a real population.method. We performed a retrospective cohort study of ACS patients who underwent PCI and were discharged for clopidogrel, ticagrelor, or prasugrel between 2012 and 2018 at Kaiser Permanente, Northern California. We used Cox proportional hazards models with propensity score adjustment to assess the association between P2Y12 and the primary outcomes of all-cause mortality, myocardial infarction (MI), stroke, and bleeding.the results. 15,476 patients participated in the study (93.1% treated with clopidogrel, 3.6% with ticagrelor and 3.2% with prasugrel). Compared to the clopidogrel group, patients treated with ticagrelor and prasugrel were younger and had fewer comorbidities. In multivariate models with propensity index adjustment, we found a lower risk of all-cause mortality in the ticagrelor group compared with the clopidogrel group (HR (95% CI) 0.43 (0.20-0.92) ), but no difference in other endpoints and there is no difference between prasugrel and clopidogrel in any endpoint. A higher proportion of patients on ticagrelor or prasugrel switched to an alternative P2Y12 drug compared to clopidogrel ( <0.01), and a higher level of persistence was observed in patients on clopidogrel compared to ticagrelor ( =0.03) or prasugrel ( <0.01).Application. Among patients with ACS undergoing PCI, we observed a lower risk of all-cause mortality in patients treated with ticagrelor compared with clopidogrel, but no difference in other clinical endpoints or differences in endpoints between prasugrel and clopidogrel. These results suggest that further research is needed to identify the optimal P2Y12 inhibitor in the real population.
Data from randomized studies have shown an approx. 2% reduction in ischemic events and a 0.5–1% increase in bleeding with ticagrelor or prasugrel compared with clopidogrel in patients with acute coronary syndrome (ACS) [1,2]. These data have not been equally replicated in real non-clinical trial populations [3–5]. The largest of these studies evaluated ticagrelor versus clopidogrel and showed that the 1-year risk of net adverse clinical events did not differ between groups after propensity index adjustment, with higher rates of bleeding and dyspnea in the ticagrelor group.3]. In this study, our aim was to determine the comparative efficacy and safety of novel P2Y12 inhibitors versus clopidogrel in a large integrated healthcare system among ACS patients undergoing percutaneous coronary intervention (PCI).
2.1. Survey the population
Kaiser Permanente Northern California (KPNC) is an integrated health system that provides comprehensive care to more than 4.5 million members in Northern California. Health Plan owns and operates 21 medical centers, including more than 250 outpatient facilities, pharmacies and laboratories, providing comprehensive inpatient, acute and outpatient care, nearly all of which are captured by an electronic health record (EHR) system integrated into all practice settings. KPNC members generally represent the California population in terms of ethnic and socioeconomic profile . The study population included patients undergoing PCI for ACS at twelve regional cardiac catheterization laboratories in KPNC between January 1, 2012 and December 31, 2018. This start date was chosen because ticagrelor, which is the newer of the two new drugs, was approved by the FDA in 2011. The study was approved by the KPNC Institutional Review Board with a waiver of consent.
ACS PCI cases were initially identified from the American College of Cardiology/National Cardiovascular Data Registry (ACC/NCDR) database from the KPNC Cardiac Catheterization Laboratory . Exclusion criteria included (1) age less than 18 years at the time of PCI, (2) less than 120 days of drug insurance membership before PCI, (3) P2Y12 inhibitors dispensed within 120 days before PCI, (4) less than 12 monthly drug insurance membership after discharge unless death within 1 year, (5) death within 30 days of discharge, (6) no record of P2Y12 inhibitor dispensed within 30 days of discharge, (7) two different P2Y12 drugs dispensed on same day after discharge and (8) patients prescribed ticlopidine (Fig.1). The index event was assigned as the first qualifying ACS event admitted during the study period.
Cohort Team Consortium Diagram.
The use of P2Y12 antagonists was achieved electronically using previously proven methods . Briefly, patients were assigned to receive one of the three P2Y12 antagonists if they had a record of administration of ticagrelor, prasugrel, or clopidogrel within 30 days of hospital discharge for PCI.
Adherence, persistence and change of P2Y12 inhibitors were assessed using predefined methods . Adherence or medication adherence (MRA) was defined as the total number of drug supply days in a year divided by 365 and expressed as a percentage. Patients with MRA >80% were defined as cooperative. We considered patients “nonpersistent” if the interval between refills was greater than supply days plus the 15-day grace period. Change was defined as more than one P2Y12 inhibitor in the first 365 days. For subjects who switched P2Y12 inhibitors during the trial, all P2Y12 load information was included in the calculation of adherence and durability (i.e.,
Primary study outcomes included all-cause mortality, in-hospital myocardial infarction, in-hospital stroke, and in-hospital bleeding assessed within the first year of the index ACS event. All inpatient events were defined by ICD codes with a primary, primary, or secondary diagnosis during hospitalization. Patients were followed from the index event until death, the outcome of interest, or up to one year, whichever occurred first. All inpatient outcomes were pooled independently (eg, patients who had an inpatient stroke were still followed for other outcomes).
2.4. Data collection
Basic demographic, laboratory, procedural, and PCI index drug use data were extracted from various KPNC electronic databases, including variables submitted to the Cath PCI ACC/NCDR Quality Registry as defined in version 4.4 and version 5 . Baseline comorbidities were identified using ICD-9 and 10 code definitions within a year before the index event. Laboratory data were obtained at the time of cardiac catheterization or the last values within a day before the procedure. Use of other cardiac medications was observed within 30 days of the index event. In addition, the PRECISE DAPT score, a validated score for predicting post-stent bleeding risk, was calculated for each patient .
2.5. Statistical analysis
Descriptive statistics were used to describe demographic and clinical characteristics of the P2Y12 inhibitor cohort. We used clopidogrel as the reference group and we compared ticagrelor or prasugrel with clopidogrel. Differences in performance were assessed on a duplicate basisT- test for continuous variables and chi-square test for categorical variables. These assays were also used to assess differences in adherence, persistence, and switching between new P2Y12 inhibitors and clopidogrel from the index event to 1-year follow-up. Trends in the use of P2Y12 inhibitors during the study period were assessed using the Cochran-Mantel-Haenszel test.
We used the Kaplan-Meier (KM) method to analyze patient outcomes during one-year follow-up. Comparisons between patients receiving different P2Y12 inhibitors were made using log-rank tests. We calculated the hazard ratio (HR) and 95% confidence interval (CI) for the association between P2Y12 inhibitor use and each outcome using bivariate and multivariate Cox proportional hazards (PH) regression models. Covariates for multivariate models were selected a priori based on previously published studies, clinical significance, or values <0.1 from bivariate analyzes assessing demographic and clinical characteristics and P2Y12 inhibitor use. We performed two adjustment steps, first including all potential covariates in the multivariate models, and then removing those covariates that had no significant association (ie, per research question.
Because the choice of P2Y12 inhibitor may be associated with other prognostic factors, we also performed propensity score (PS) adjustment using the optimal variable ratio matching method to balance the groups at baseline. Each patient in the ticagrelor or prasugrel group was matched with patients in the clopidogrel group with a minimum match of 1:1 and a maximum of 1:5. The clamp width was 0.25. Baseline variables selected for PSM included age, gender and all clinical risk factors shown in table < 0.11(ie all cardiovascular and risk factors, smoking, chronic kidney disease, chronic lung disease and indications for PCI). These variables are also controlled for in subsequent multivariate models, with additional variables considered statistically significant in unadjusted analysis or clinically significant. This study was presented as an abstract at the Society for Cardiovascular Angiography and Interventions (SCAI) conference in May 2022 . During manuscript preparation, it was noted that hypertension was inadvertently omitted from the statistical models (both multivariate and propensity matching) for the summary. As hypertension is an important risk factor that needs to be corrected, we made sure to add it to the models and repeat the analysis – this explains the results in the manuscript that are inconsistent with the abstract.
Baseline karakteristika, ticagrelor og prasugrel versus clopidogrel.
All data extraction and analyzes were performed using SAS 9.4 (Cary, North Carolina).
We identified 15,479 patients who met all inclusion and exclusion criteria. Of these, 93% did not receive clopidogrel, 3.6% ticagrelor and 3.2% prasugrel. Clopidogrel use decreased over time from 94.7% of all dispensed in 2012 to 88.2% in 2018, while ticagrelor use increased from 0% to 10.2% and prasugrel use decreased from 5.3% to 1.5% ( < 0.001) (Fig.2).
Changes in the use of P2Y12 inhibitors during the study period 2021-2018. Trends over time were assessed using the Cochran-Mantel-Haenszel z-test
The mean age at PCI index was 66.3 (standard deviation [SD] ± 12.0) years, and 27.8% of the cohort was female ( Table 1 ).1). Compared with the ticagrelor or prasugrel groups, the clopidogrel group was older, had a higher proportion of patients, had a more significant cardiovascular history such as previous CABG, cerebrovascular disease, and heart failure, and had more comorbidities, such as chronic kidney disease and hypertension (all < 0, 05). In addition, the group receiving clopidogrel had lower hemoglobin and platelet counts compared to the group receiving ticagrelor or prasugrel ( <0.001). A greater percentage of patients in the prasugrel (40.7%) or ticagrelor (49.8%) groups had ST-segment elevation myocardial infarction (STEMI) as an indication for PCI compared with clopidogrel (20%), and a greater proportion of these patients were like emergencies and cardiogenic shock. Patients on clopidogrel also had more PCI with vein grafting, as well as higher PRECISE DAPT scores, and were more likely to use concomitant oral anticoagulants. Table2shows baseline characteristics of the propensity-matched population and supplementary tables1aand1bshows characteristics of patients treated with clopidogrel who were excluded from the ticagrelor and prasugrel sensitivity matching.
Baseline characteristics after propensity adjustment.
Adherence to P2Y12 inhibitor therapy was similar in all three groups (Table3). However, a greater proportion of patients taking the new P2Y12 inhibitors switched medications during follow-up, with the majority (92%) switching to clopidogrel. Additionally, treatment persistence was lower in the prasugrel plus ticagrelor group compared to the clopidogrel group ( <0.03 for ticagrelor vs. clopidogrel; <0.001 for prasugrel vs. clopidogrel).
Changes in drug use from index to 12-month follow-up.
After 1 year of follow-up, the clopidogrel group had higher mortality than the ticagrelor group (<0.01) (Table)4). The rates of myocardial infarction, stroke and bleeding were similar in all three groups. Kaplan-Meier curves for the results are included in the Supplementary Figure1. Table 5 shows the frequency of side effects in the propensity to match population.
One year of adverse events.
When propensity and multivariate adjustment were combined, ticagrelor was associated with a lower risk of all-cause mortality compared with clopidogrel (adjusted HR 0.43, 95% CI, 0.20–0.92) (Table)6). There were no differences in myocardial infarction, stroke or bleeding between the ticagrelor and clopidogrel groups. Similarly, after adjustment, there were no differences between the clopidogrel and prasugrel groups in the risk of death, myocardial infarction, stroke, or bleeding.
One-year rates of adverse events in a propensity-matched population.
After combining multiple variables and adjusting for the propensity of patients undergoing PCI for ACS, ticagrelor compared with clopidogrel was associated with a lower risk of all-cause mortality but similar rates of in-hospital myocardial infarction, stroke, and bleeding. We found no difference between prasugrel and clopidogrel in any of the side effects.
In the pivotal PLATO randomized trial comparing ticagrelor with clopidogrel in ACS, researchers found a similar lower risk of all-cause mortality with ticagrelor, but also a lower risk of myocardial infarction and vascular death.1]. In our study, without differences in the rate of myocardial infarction or stroke, it is difficult to determine the mechanism of the associated differences in all-cause mortality. Several similar observational studies have not shown an association between new P2Y12 inhibitors and myocardial infarction, despite showing it in randomized controlled trials, while others have replicated some of the results.3–5,11–14].
Randomized trials, the gold standard for isolating treatment effect while reducing bias, create sparse settings that do not necessarily reflect daily patient care. For example, PLATO excluded patients on oral anticoagulants, patients on dialysis, patients with clinically significant thrombocytopenia and anemia, and "any other condition that could endanger the patient or affect the outcome of the study in the opinion of the investigator (eg, cardiogenic shock, severe hemodynamic instability, active cancer).In addition, all conditions that increase the risk of non-compliance or loss of control are excluded.
Probni TRITON TIMI 38, , which led to the approval of prasugrel for ACS patients undergoing PCI, similarly has a number of exclusion criteria including, but not limited to, cardiogenic shock, NYHA class IV congestive heart failure, “clinical findings, at the discretion of investigator, associated with an increased risk of bleeding," history of hemorrhagic stroke, ischemic stroke within 3 months, platelet count less than 100,000, anemia (hemoglobin <10 g/dl) at screening, concomitant oral anticoagulants, known severe liver dysfunction, and "a concurrent medical illness that the researchers believe is associated with reduced survival during the expected treatment period."
These protocols exclude many important patient phenotypes. For example, in our study there were 218 patients with cardiogenic shock, 3201 patients with heart failure, 1136 with liver disease, 420 on dialysis and 1563 on oral anticoagulants. There is also less ethnic diversity in the randomized trials, with >90% of participants in the PLATO and TRITON TIMI 38 trials being white compared with more than one-third of our non-white patient population.
A greater proportion of patients in the ticagrelor and prasugrel group switched medications compared to the clopidogrel group, with the majority switching to clopidogrel. Both ticagrelor and prasugrel have a higher price  so this could have played a role and there is a potential risk of stent thrombosis if the change is not made early enough after stent placement . Also, a higher proportion of patients on clopidogrel were persistent compared with ticagrelor and prasugrel, an observation previously reported  and which also affects treatment performance, as premature discontinuation of antiplatelet drugs has been identified as the single most important predictor of stent thrombosis .
Our study has a number of limitations. This was an observational study and treatment with P2Y12 inhibitors was not randomized. Any differences or lack of differences found in our study may still be influenced by unmeasured confounding factors. The larger sample size of patients on clopidogrel compared with ticagrelor and prasugrel may limit the statistical power of the analysis. Furthermore, the use of aspirin was not available in the pharmacy database.
Determination of exposure, i.e. for the P2Y12 inhibitor, was based on pharmacy records. Pill counts may have provided a more accurate estimate of thienopyridine consumption, but the use of filled prescriptions has been shown to reflect actual drug use in patients with high accuracy .
In patients undergoing PCI for acute coronary syndrome, after adjustment for multivariate and propensity, ticagrelor compared with clopidogrel was associated with lower all-cause mortality but similar rates of myocardial infarction, stroke, and bleeding, whereas prasugrel compared with clopidogrel was associated with similar rates . of all clinically relevant outcomes examined. In addition, patients who initially received new P2Y12 inhibitors switched treatment more often and were less patient with treatment. Further randomized controlled trials and those involving more patients in real-world practice are needed to clarify these effects.
Hazard ratio (HR) and 95 confidence interval (CI) comparing the effect of new P2Y12 inhibitors (ticagrelor or prasugrel) with clopidogrel on adverse events at 1-year follow-up.
Availability of data
Data used to support the findings of this study are available from the corresponding author upon request.
Conflict of interest
The authors declare that they have no conflict of interest.
This research was supported by Kaiser Permanente Northern California Community Health; Oakland, CA 1502346-3.
Supplementary Figure 1. Kaplan–Meier curves for clopidogrel, prasugrel, and ticagrelor for all outcomes measured. Supplementary Table 1(a). Baseline characteristics of excluded patients on clopidogrel after ticagrelor adjustment. Supplementary Table 1(b). Baseline characteristics of excluded patients on clopidogrel after matching with prasugrel.(Additional materials)
Copyright © 2023 Amit Sachdeva et al. This is an open access article distributed under the nameNaming the Creative Commons license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.