Abstract
Background
Prasugrel and ticagrelor have demonstrated higher efficacy than clopidogrel in their main clinical trials for patients with acute coronary syndrome (ACS). However, the long‐term prognosis and different clinical characteristics related to the type of antiplatelet prescription in current clinical practice ACS patients have not been analysed in depth. The objective of this study was to analyse the clinical profile of ACS and the efficacy and safety of novel oral P2Y12 inhibitors in current clinical practice patients discharged afterACS.
Methods
We collected data from the ACHILLES registry, and an observational, prospective and multicentre registry of patients discharged after ACS. We analysed baseline characteristics, clinical profile and therapy during ACS admission and compared with the different treatments at discharge. After 1 year of follow‐up, ischaemic and major bleeding events were analysed. Multivariate Cox regression analysis and Kaplan Meier curves were also plotted.
Results
Of 1717 consecutive patients, 1294 (75.4%) were discharged with a P2Y12 inhibitor without oral anticoagulation. Novel oral P2Y12 inhibitors were indicated in 47%. Patients treated with clopidogrel were elderly (69.1 ± 13.4 vs 60.4 ± 11.5 years; P < .001) and had a higher prevalence of cardiovascular risk factors. GRACE and CRUSADE scores were higher in the clopidogrel than in novel oral P2Y12 inhibitors group (P < .001). After 1 year of follow‐up, 64(5.0%/year) patients had a new myocardial infarction, 127(10.0%/year) had a major adverse cardiovascular event (MACE) and 78(6.1%/year) died. Patients treated with clopidogrel had a significantly higher annual rate of cardiovascular mortality, MACE and all‐cause mortality (allP < .001) without differences in major bleeding (P = .587) compared with novel oral P2Y12 inhibitors. After multivariate adjustment for the main clinical variables related to adverse prognosis in ACS patients, the discharge with novel oral P2Y12 inhibitors therapy was independently associated with lower risk of all‐cause mortality (HR0.49, 95% CI [0.24‐0.98], P = .044) and lower risk of MACE (HR0.64, 95% CI [0.41‐0.98], P = .044).
Conclusions
In this prospective, observational and current clinical practice ACS registry, the use of novel oral P2Y12 inhibitors was associated with a reduction in adverse events compared with clopidogrel in patients with ACS. Novel oral P2Y12 inhibitors prescription at discharge was independently associated with lower all‐cause mortality and MACE without differences in bleeding events. However, clopidogrel remained the most common P2Y12 inhibitor employed for ACS, especially in older and high‐risk patients.
Keywords: acute coronary syndrome, clopidogrel, myocardial infarction, P2Y12 inhibitors, prasugrel, ticagrelor
What is already known about this subject
Dual antiplatelet therapy is critical in patients with acute coronary syndrome (ACS).
Clinical guidelines recommend ticagrelor and prasugrel use in ACS patients.
Current clinical practice data for the effectiveness and safety of those drugs is unknown.
What this study adds
Ticagrelor and prasugrel are associated with a reduction in adverse events compared to clopidogrel.
No differences in bleeding events compared to clopidogrel.
Despite clinical guidelines, clopidogrel remains the main P2Y12 agent in elderly and high‐risk patients.
1. INTRODUCTION
Acute coronary syndrome (ACS) is a clinical condition with a high risk of mortality and morbidity in developed countries. The physiopathology of this entity involves the rupture of an atherosclerotic plaque and the platelet aggregation contributes to partial or total occlusion of the coronary artery.1 The use of dual antiplatelet therapy (DAPT), a combination of acetylsalicylic acid (ASA) and a P2Y12 inhibitor, is critical in patients with ACS or after a percutaneous coronary intervention (PCI).2, 3, 4, 5 For many years, DAPT has consisted of the association of ASA and clopidogrel, but in recent years the presence of the novel P2Y12 inhibitors prasugrel and ticagrelor 6, 7 has substantially improved the therapeutic options in antiplatelet therapy. These drugs are more potent, effective and produce greater inhibition of platelets than clopidogrel, with faster activation. Due to the consistent superiority of these novel P2Y12 inhibitors compared to clopidogrel in clinical trials,8 the clinical guidelines recommend their use in patients with ACS (class IA).9, 10, 11, 12, 13 One of the most important points is to know the optimal duration of DAPT.14 The most recent European Society of Cardiology (ESC) clinical guidelines have proposed different risk scores (PRECISE‐DAPT and DAPT) to assess ischemic and bleeding risk, and to shorten or lengthen the duration of DAPT.4
Recently, the association of ticagrelor with a lower risk of death, myocardial infarction or stroke in a group of patients with previous myocardial infarction, compared to others who were treated with clopidogrel, has been reported.15 Ticagrelor showed much more potent platelet inhibition compared with clopidogrel in high‐risk patients, and patients with Non ST‐segment elevation acute coronary syndrome (NSTE‐ACS) and chronic kidney disease.16 Indeed, Weisshaar etal performed a trial to evaluate the effect of ticagrelor on endothelial dysfunction and observed that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion.17 However, the clinical profile of patients admitted with ACS and treated with new oral P2Y12 inhibitors and the hypothetical reduction of ischemic adverse events during the follow‐up or the risk of major bleeding with both drugs in current clinical practice of ACS patients are unknown.
The aim of this study was to analyse the clinical profile of ACS patients treated with the novel P2Y12 inhibitors prasugrel and ticagrelor, and the efficacy and safety in terms of adverse events during the follow‐up in the current clinical practice management of patients discharged after admission forACS.
2. MATERIAL AND METHODS
The data, analytic methods and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure because some materials are used for other unpublished projects.
2.1. Study design
The ACHILLES (Spanish acronym for AntiagregaCion en HospItales deL Levante ESpanol) registry is an observational, prospective, multicentre registry of consecutive patients. It was designed to analyse the use, efficacy and safety of antiplatelet therapy in patients discharged after ACS, from February 2014 to December 2015. Especial attention was paid to the type of P2Y12 inhibitors use at discharge (clopidogrel, ticagrelor or prasugrel).18 This registry involved three tertiary care hospitals with cardiac catheterization laboratories. Clinical and previous demographical characteristics were collected for patients included in the ACHILLES registry. At entry, the results of blood samples were collected, as well as the type of ACS [STEMI (ST‐segment elevation myocardial infarction) or NSTE‐ACS (non ST‐segment elevation acute coronary syndrome) that includes unstable angina and NSTEMI (non ST‐segment elevation myocardial infarction)], type of management of ACS (medical therapy only or concomitant invasive treatment), echocardiography and angiography findings, all drugs employed during the admission and at discharge (with special attention to antithrombotic therapy), and the reasons for discontinuation during the follow‐up. The ischaemic and bleeding risk of all the patients included in the ACHILLES registry were calculated using the GRACE19 and CRUSADE20 scores.
After 1 year of follow‐up, all adverse clinical events were collected: stroke (defined as a focal neurological loss of ischemic or haemorrhagic origin with residual deficit of at least 24 hours), myocardial infarction (defined by the universal definition of 200721), all‐cause mortality, cardiovascular mortality and major adverse cardiovascular events (MACEs), including the composite of cardiovascular mortality, nonfatal myocardial infarction and nonfatalstoke/ischaemic transitory attack. Bleeding events were also assessed following the Bleeding Academic Research Consortium (BARC) criteria22 and major Thrombolysis in myocardial infarction (TIMI) criteria.23 The follow‐up was performed as follows: face‐to‐face visit at discharge and telephone or face‐to‐face contact at 3 months, 9 months and after 1 year of follow‐up after discharge.
To assess the bleeding risk of patients and the relationship of adverse prognosis during the follow‐up, we also calculated the PRECISE‐DAPT risk score for every patient using the modified nomogram of Costa etal.24 without white blood cell count.4
2.2. Study population
All patients ≥18 years discharged with a diagnosis of any form of ACS (STEMI or NSTE‐ACS following the ESC clinical guidelines criteria9, 10) were consecutively included. Patients with ACS during another extracardiac disease (stroke, sepsis, severe anaemia, hypoxemia, surgery or trauma) were excluded from this study. We also excluded patients who died during hospitalization. The ACHILLES registry is an observational and voluntary registry of patients with ACS. All patients provided signed informed consent and were treated according to current clinical practice without any influence on their diagnosis or therapeutic management. Those patients who refused informed consent were excluded. In this subanalysis of the ACHILLES registry, and in order to avoid bias, patients with oral anticoagulation were excluded.
Our study protocol was conducted according to the Helsinki Declaration and Good Clinical Practice Guidelines25 and was approved by the Department for Medicinal Products for Human Use of the Spanish Agency for Medicines and Health Products with resolution of Post‐Authorization Study‐Other Designs (reference JRN‐NAG‐2014‐01). Adverse events were collected by all the scientific members of the ACHILLES registry following the standard definitions of adverse events in clinical guidelines and approved by ethical committee. Indeed, to guarantee the truthfulness of the results and to avoid any type of bias in the adverse events collected during the follow‐up, an external independent audit of the registry data (independent clinical research organization) was performed evaluating the correct inclusion of the patients, data analysed, compliance with ethical principles and the possible existence of patients not included during the recruitment period in all the participating hospitals.
2.3. Statistical analysis
Categorical variables were expressed as frequencies (percentages). The comparison of discrete variables was carried out with the χ 2 test. The Kolmogorov‐Smirnov test was used to determine if the continuous variables followed a normal distribution. Quantitative or continuous variables were expressed as mean (±SD). Comparison of the groups for the continuous variables was performed with the Student's ttest. Multivariate Cox regression analysis, which included variables that demonstrated a significant association in the univariate analysis (P < .150), determined those that showed independent association with the presentation of MACE, all‐cause mortality and major bleeding, calculating the hazard ratio (HR)with a 95% confidence interval and statistical significance in each case. Differences in event‐free survival were examined with the log‐rank test and Kaplan‐Meier curves were drafted accordingly. We also analysed subgroups models to analyse the effect of novel P2Y12 inhibitors in high‐risk patients and the results were expressed with hazard ratio and Pvalue for interaction. A Pvalue of <.05 was considered statistically significant. Statistical analyses were performed using the statistical software package SPSS version 20.0 (SPSS Inc., Chicago, IL, USA).
2.4. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY.
3. RESULTS
A total of 1853 patients were admitted with ACS during the 2‐year period of enrolment. One hundred and thirty patients died during the hospitalization and six patients refused informed consent. Finally, 1717 consecutive patients were included in the ACHILLES registry. Of these, 1294 (75.3%) were discharged only with DAPT (aspirin plus P2Y12 inhibitor) without oral anticoagulation (see Supporting Information Fig.S1).
The baseline characteristics of the population are shown in Table 1. The mean age of the population was 65.0 ± 13.3 years and 73.6% of patients were male. In this population 19.9% of patients had a diagnosis of unstable angina, 42.3% of NSTEMI and 37.8% of STEMI. According to the management of ACS, 18.8% ofpatients had only medical management and 73.7% of patients had complete revascularization. At discharge, the use of P2Y12 was as follows: 686 (53.0%) patients with clopidogrel and 608 (47.0%) patients with novel P2Y12 inhibitors (192 patients (14.8%) with prasugrel and 416 patients (32.1%) with ticagrelor).
Table 1.
Comparison of baseline characteristics between antiplatelet therapy in global population during hospital admission
| Variable | Total (%) n = 1294 | Clopidogrel n = 686 | Novel P2Y12 inhibitors n = 608 | P value |
|---|---|---|---|---|
| Age | 65.0 ± 13.3 | 69.1 ± 13.4 | 60.4 ± 11.5 | <.001 |
| Male | 953 (73.6%) | 484 (70.6%) | 469 (77.1%) | .008 |
| Hypertension | 834 (64.5%) | 476 (69.5%) | 358 (58.9%) | <.001 |
| Dyslipidaemia | 761 (58.8%) | 414 (60.3%) | 347 (57.1%) | .235 |
| Diabetes mellitus | 475 (36.7%) | 283 (41.3%) | 192 (31.6%) | <.001 |
| Active smoker | 528 (40.9%) | 231 (33.8%) | 297 (48.8%) | <.001 |
| Previous coronary disease | 318 (24.6%) | 197 (28.7%) | 121 (19.9%) | <.001 |
| Previous stroke | 96 (7.4%) | 75 (10.9%) | 21 (3.5%) | <.001 |
| Haemoglobin | 13.7 ± 2.0 | 13.4 ± 2.1 | 14.3 ± 1.7 | <.001 |
| Creatinine clearance | 80.3 ± 29.3 | 74.1 ± 29.8 | 88.2 ± 27.5 | <.001 |
| LVEF | 56.9 ± 10.9 | 56.2 ± 11.3 | 56.9 ± 10.4 | .210 |
| GRACE 6 months | 111.7 ± 33.7 | 117.9 ± 35.7 | 106.1 ± 30.5 | <.001 |
| CRUSADE | 28.4 ± 15.6 | 31.7 ± 16.7 | 23.9 ± 13.1 | <.001 |
| Diagnosis at discharge | <.001 | |||
| Unstable angina | 258 (19.9%) | 175 (67.8%) | 83 (32.2%) | |
| NSTEMI | 547 (42.3%) | 325 (59.4%) | 222 (40.6%) | |
| STEMI | 489 (37.8%) | 186 (38.0%) | 303 (62.0%) | |
| Catheterization performed | 1214 (93.8%) | 612 (89.2%) | 602 (99%) | <.001 |
| Type of catheterization | <.001 | |||
| No. requested | 80 (6.2%) | 74 (10.8%) | 6 (1%) | |
| Urgent | 495 (38.3%) | 179 (26.1%) | 316 (52.0%) | |
| 24‐48 hours | 420 (32.5%) | 234 (34.1%) | 186 (30.6%) | |
| >48 hours | 299 (23.1%) | 199 (29.0%) | 100 (16.4%) | |
| Type of treatment | <.001 | |||
| Medical treatment | 243 (18.8%) | 202 (29.4%) | 41 (6.7%) | |
| PCI | 1003 (77.5%) | 442 (64.4%) | 561 (92.3%) | |
| Coronary surgery | 48 (3.7%) | 42 (6.1%) | 6 (1%) | |
| Complete revascularization | 773 (73.7%) | 345 (71.4%) | 428 (75.6%) | .140 |
| Use of drug‐eluting stent | 784 (79.3%) | 323 (74.6%) | 461 (82.9%) | .002 |
| Number of stents used | 1.76 ± 1.1 | 1.70 ± 1.1 | 1.81 ± 1.1 | .265 |
| Length of stents | 34.0 ± 24.2 | 32.6 ± 23.4 | 35.0 ± 24.8 | .094 |
| Medical therapy at discharge | ||||
| ASA at discharge | 1275 (98.5%) | 668 (97.4%) | 607 (99.8%) | <.001 |
| P2Y12 inhibitor at discharge | <.001 | |||
| Clopidogrel | 686 (53%) | 686 (100%) | 0 (0%) | |
| Prasugrel | 192 (14.8%) | 0 (0%) | 192 (31.6%) | |
| Ticagrelor | 416 (32.1%) | 0 (0%) | 416 (68.4%) | |
| Beta‐blockers | 1086 (84%) | 551 (80.4%) | 535 (88%) | <.001 |
| Statins | 1251 (96.8%) | 654 (95.5%) | 597 (98.2%) | .006 |
| ACEI/ARB | 1053 (81.4%) | 517 (75.4%) | 536 (88.2%) | <.001 |
Data are presented as observed number and percentage (%), mean ± SD or median (IQR: Interquartile range).
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetyl salicylic acid; LVEF, left ventricular ejection fraction; NNSTEMI, non ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST‐segment elevation myocardial infarction.
Patients treated with clopidogrel were older (69.1 ± 13.4 vs 60.4 ± 11.5 years; P < .001) and had higher prevalence of the main cardiovascular factors (hypertension, diabetes mellitus, previous coronary disease and previous stroke, all P < .001) compared to patients treated with novel P2Y12 inhibitors. Patients treated with clopidogrel had also higher ischemic risk evaluated by GRACE score (117.9 ± 35.7 vs 106.1 ± 30.5; P < .001) and bleeding risk assessed by CRUSADE score (31.7 ± 16.7 vs 23.9 ± 13.1; P < .001) compared with patients treated with prasugrel or ticagrelor.
The use of novel P2Y12 inhibitors was higher in STEMI patients (62.0%), whereas the use of clopidogrel increased in patients with diagnosis of unstable angina (67.8%). In patients with only medical management of ACS, clopidogrel was the most common antiplatelet treatment prescribed (83.1% of patients), while novel P2Y12 inhibitors were prescribed in 55.9% of patients revascularized with angioplasty (P < .001).
3.1. Adverse events and survival analyses
The follow‐up was completed in 98.1% of the patients included in the ACHILLES registry. After 1 year of follow‐up, 64(5.0%/year) patients had a new myocardial infarction, 127(10.0%/year) had a MACE and 78(6.1%/year) patients died. The distribution of the adverse events according to the P2Y12 inhibitor therapy at discharge is summarized in Table 2. Patients treated with clopidogrel had significantly higher annual rate of myocardial infarction (3.7% vs 6.3%; P = .038), cardiovascular mortality (5.7% vs 1.3%; P < .001), MACE (13.6% vs 6.0%; P < .001) and all‐cause mortality (9.6% vs 2.3%; P < .001) compared with prasugrel or ticagrelor therapy, without differences in major bleeding (P = .587). We did not observed differences for major bleeding between clopidogrel orticagrelor/prasugrel assessed by BARC 3‐5 (3.0% vs 1.3%; P = .193), clinical significant bleeding BARC 2‐5 (8.2%vs 6.2%; P = .495) or major bleeding by TIMI (1.2% vs 0.8%; P = .587 (Table 2).
Table 2.
Distribution of adverse events according to antiplatelet therapy after 1 year of follow‐up
| Overall (n = 1270) | Clopidogrel (n = 670) | Novel P2Y12 inhibitors (n = 600) | P value | |||
|---|---|---|---|---|---|---|
| Ischaemic stroke | 17 | 6 | 11 | .464 | ||
| Annual rate (%/year) | 1.3%/year | 1%/year | 1.6%/year | |||
| Acute myocardial infarction | 64 | 42 | 22 | .038 | ||
| Annual rate (%/year) | 5.0%/year | 6.3%/year | 3.7%/year | |||
| Cardiovascular mortality | 46 | 38 | 8 | |||
| Annual rate (%/year) | 3.6%/year | 5.7%/year | 1.3%/year | <.001 | ||
| MACE | 127 | 91 | 36 | <.001 | ||
| Annual rate (%/year) | 10.0%/year | 13.6%/year | 6.0%/year | |||
| All‐cause mortality | 78 | 64 | 14 | |||
| Annual rate (%/year) | 6.1%/year | 9.6%/year | 2.3%/year | <.001 | ||
| Bleeding events | ||||||
| BARC 1‐5 | 176 | 65 | 51 | |||
| Annual rate (%/year) | 9.1%/year | 9.7%/year | 8.5%/year | .587 | ||
| BARC 2‐5 | 92 | 55 | 37 | |||
| Annual rate (%/year) | 7.2%/year | 8.2%/year | 6.2%/year | .495 | ||
| BARC 3‐5 | 28 | 20 | 8 | |||
| Annual rate (%/year) | 2.2%/year | 3%/year | 1.3%/year | .193 | ||
| Bleeding events‐TIMI major | 13 | 8 | 5 | .587 | ||
| Annual rate (%/year) | 1%/year | 1.2%/year | 0.8%/year | |||
Abbreviations: BARC, Bleeding Academic Research Consortium; MACE, major adverse cardiovascular event; TIMI (Thrombolysis in myocardial infarction).
Univariate and multivariate analyses were also performed (Table 3 and Supporting Information TablesS1‐S3). On multivariateCox regression analysis, the discharge with novel P2Y12inhibitors was independently associated with lower risk of all‐cause mortality (HR0.49, 95% CI [0.24‐0.98], P = .044) and lower risk of MACE (HR0.64, 95% CI (0.41‐0.98), P = .044]. The independent effect was observed despite being adjusted for othermortality‐risk reduction drugs such as beta‐blockers or angiotensin inhibitors. The use of novel oral P2Y12 inhibitors was not an independent predictor of major bleeding (BARC 3‐5) or clinical significant bleeding (BARC 2‐5) (Supporting Information TablesS3 and S4).
Table 3.
Independent predictors of adverse clinical events by multivariate Cox regression analysis
| HR | 95% CI | P value | |
|---|---|---|---|
| All‐cause mortality | |||
| Novel P2Y12 inhibitors | 0.49 | 0.24‐0.99 | .043 |
| Haemoglobin | 0.87 | 0.76‐0.99 | .037 |
| GRACE score | 1.02 | 1.01‐1.04 | <.001 |
| MACE | |||
| Novel P2Y12 inhibitors | 0.65 | 0.43‐0.99 | .049 |
| NSTEMI | 1.96 | 1.22‐3.15 | .005 |
| GRACE score | 1.02 | 1.01‐1.03 | <.001 |
| Bleeding BARC 3‐5 | |||
| Age | 1.07 | 1.01‐1.14 | .019 |
| Haemoglobin | 0.75 | 0.61‐0.94 | .010 |
Abbreviations: BARC, Bleeding Academic Research Consortium; CI, confidence interval (for detailed multivariate analysis adjusted by different variables see Supporting Information Tables); HR, hazard ratio; MACE, major adverse cardiovascular event; NSTEMI, nonST‐elevation myocardial infarction.
Kaplan‐Meier curves analysis showed that in patients with ACS, the use of clopidogrel was significantly associated with high all‐cause mortality, cardiovascular mortality and MACE (all log‐rank P < .001) without differences for major bleeding compared with novel oral P2Y12 inhibitors therapy (Figure 1). We also performed subgroup analysis to determine the effect of these novel P2Y12 inhibitors over patients at high risk of cardiovascular events: diabetic, STEMI and NSTE‐ACS patients. In all groups, we observed the same results, with significant Pinteraction value, where patients treated with clopidogrel had higher risk of cardiovascular events without differences in major bleeding (Supporting Information Figs S2‐S4).
Figure 1.
Kaplan‐Meier survival curves for different events, comparing clopidogrel versus novel P2Y12 inhibitors. BARC, Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event; TIMI (Thrombolysis in myocardial infarction).
Regarding the PRECISE‐DAPT score, we had 648(56%) patients with low risk (<17 points), 112(9.7%) patients with moderate risk (18‐24 points) and 395(34.2%) patients with high risk (>25). We calculated the risk of major bleeding assessed by BARC 3‐5 and observed that low‐risk patients had a 0.77%/year risk of bleeding, moderate‐risk patients had a 1.80%/year risk of bleeding and high‐risk patients presented a 4.60%/year risk of developing a major bleeding event. We also assessed the predictive performance of the PRECISE‐DAPT score for major bleeding and in the ACHILLES population showed that the PRECISE‐DAPT score had good predictive performance for major bleeding (c‐statistic 0.768, 95% CI [0.697‐0.839], P < .001). Kaplan‐Meier curves analysis showed that patients with a high PRECISE‐DAPT score had significantly more major bleeding events compared with patients with a low PRECISE‐DAPT score (HR6.18, 95% CI [2.29‐16.6], P < .001) (Supporting Information Fig.S5a,b).
4. DISCUSSION
In this prospective, observational and current clinical practice ACS registry, the use of prasugrel or ticagrelor was associated with a lower adverse event rate compared with clopidogrel in patients with ACS. Prescription of these novel P2Y12 inhibitors at discharge was independently associated with lower all‐cause mortality and MACE without differences in bleeding events. Nevertheless, we should highlight that clopidogrel remained the most common P2Y12 inhibitor employed for ACS, especially in older and high‐risk patients.
The ACHILLES registry showed that the real‐world management of ACS patients followed the current recommendations of the ESC clinical practice guidelines9, 10, 11, 26: cardiac catheterization performed in 94% of the population, hospital revascularization in 80.2% and use of drug‐eluting stents in 79.3% of angioplasties. The therapeutic management of ACS was one of the parameters that most influenced the choice of DAPT at discharge: in non‐revascularized patients, clopidogrel was the most widely used antiplatelet agent (83%); in contrast, prasugrel and ticagrelor were indicated primarily in percutaneously revascularized patients (56%).
However, in the use of antiplatelet agents at discharge, we observed a low guidelines adherence. Early discontinuation of antiplatelet drugs after coronary disease and PCI has been associated with an increased risk of stent thrombosis, recurrent myocardial infarction, ischemic stroke and cardiac death. Therefore, persistence with antiplatelet treatment is critical in terms of the clinical outcome of these patients.27 The percentage of novel P2Y12 inhibitors use in our registry was 47%, very similar to a recently published Italian registry, the EYESHOT study,28 where novel P2Y12 inhibitors were prescribed in 59.5% of STEMI patients and in 33.9% of ACS without ST elevation patients, and the Greek AntiPlatelet (GRAPE) Registry.29 Clopidogrel remained the most frequent P2Y12 agent in ACS patients, especially in high‐risk patients such as diabetics and patients with previous coronary disease or high GRACE score. Both GRACE and CRUSADE scores were higher in those patients treated with clopidogrel. These data reflect the “risk treatment paradox”,30 where patients in the highest risk categories are the least likely to receive the best and powerful evidence‐based medical treatments.31 Similar results were observed in the retrospective APATHY registry where clopidogrel remained the most common P2Y12 inhibitor employed for ACS and third‐generation P2Y12 inhibitor prescription was lower than expected according to guidelines recommendations.32
In two similar registries, the use of clinical risk scores in relation to selection of the antiplatelet regimen was not evaluated.29, 33, 34 In our observational registry, we analysed the ischemic and bleeding risk scores, and their score according to the treatment at discharge and we observed that patients treated with novel P2Y12 inhibitors had lower GRACE and CRUSADE scores, reflecting poor adherence to current clinical guidelines. The CRUSADE score in patients with clopidogrel was approximately 8points higher than in patients treated with prasugrel or ticagrelor. The current schemes show poor performance in predicting the development of haemorrhagic complications within the first year after ACS.35 Thus, an adequate selection of the antiplatelet agent is imperative to attempt to reduce the short and long‐term risk of adverse outcomes associated with bleeding. For this reason, the PRECISE‐DAPT score has been developed to assess bleeding risk in patients under DAPT therapy. Those patients with a high score (>25points) have a high risk of bleeding and should consider shortening the DAPT therapy. Our registry is the first time that the PRECISE‐DAPT score has been validated prospectively for BARC bleeding events with good predictive performance. This score should help clinicians in the daily clinical decision of ischemic or bleeding risk balance in patients withACS.
One of the reasons for using clopidogrel in high‐risk patients is the fear of bleeding events. We observed high use of clopidogrel in patients with a high CRUSADE score. The risk of bleeding in elderly patients with greater comorbidities is also associated with greater ischaemic risk. Recently, the Piraeus study36 described the use of clopidogrel in the elderly, in patients with greater illness and in those with greater comorbidities. This study also reflects the great variability of antiplatelet management in the population with NSTEMI and the need to obtain information from registries with standardization of events and their definitions. This under‐utilization of novel P2Y12 inhibitors in elderly patients may be explained by the lack of solid scientific evidence in terms of the risk‐benefit of novel P2Y12 inhibitors in this important subgroup or the existence of great heterogeneity among elderly patients. In our registry, patients treated with prasugrel or ticagrelor did not present differences in major bleeding rate compared to clopidogrel treatment. We observed similar results using both TIMI and BARC definitions of bleeding. Indeed, the same results were observed in diabetic patients.
We observed that diabetic patients had higher cardiovascular risk factors as well as higher GRACE and CRUSADE scores. For that reason, we performed an individual subanalysis in the diabetic population and observed that patients treated with clopidogrel had higher rate of adverse events compared with patients treated with novel P2Y12 inhibitors without differences in bleeding events. In the PROMETHEUS multicentre study37 that involved 19,919 patients, 7580 (38%) of them with diabetes, Faggioni etal37 observed that the use of prasugrel in diabetic patients after PCI‐treated ACS was lower than in non‐diabetic patients, although there were patients with high cardiovascular risk. These results are in concordance with our results. In the same way, the use of prasugrel was associated with a lower risk of mortality. Regarding ticagrelor use in diabetic patients, 6806 diabetic patients from PEGASUS‐TIMI 5438 were analysed to determine the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with diabetes and prior myocardial infarction. The authors concluded that the addition of ticagrelor to aspirin reduced cardiovascular death by 22% and coronary heart disease by 34% in diabetic patients, highlighting the importance of treating high cardiovascular risk patients with potent P2Y12 inhibitors. However, Gargiulo etal39 performed a meta‐analysis with 11,473 patients from six trials and concluded that compared with short‐term DAPT, long‐term DAPT did not reduce the risk of MACE and increased the risk of bleeding. Our results highlight the importance of using potent P2Y12 inhibitors in the first year after ACS and the necessity of assessing the benefit of long‐term DAPT in real‐world diabetic patients.
Regarding the effectiveness of antiplatelet agents, we observed greater efficacy of novel P2Y12 inhibitors with lower rates of all‐cause mortality in all patients and in the subgroups of STEMI‐NSTEMI and diabetic patients, although clopidogrel remained the main P2Y12 inhibitor. Desai etal40 observed similar results in diabetic and chronic kidney disease patients with low use of prasugrel or ticagrelor in high cardiovascular risk patients.41
In our registry, we observed that prasugrel and ticagrelor use was associated with less mortality, cardiovascular mortality and MACE compared with those patients in treatment with clopidogrel. Indeed, the use of prasugrel or ticagrelor was independently related to a reduction in adverse events without an increase in major bleeding. Sahlén etal15 in the SWEDEHEART registry demonstrated in 45,073 ACS patients that the use of ticagrelor compared with clopidogrel was associated with a lower risk of death, myocardial infarction, stroke and all‐cause mortality. Our results are comparable with these real‐world subanalyses and are consistent with the results of the main clinical trials.
5. LIMITATIONS
One of the main limitations is the observational nature of this registry. Although real‐world registries offer the best reflection of current clinical practice compared to clinical trials, the population included is usually heterogeneous, which makes it difficult to generalize the results. We included patients from three hospitals in Spain, mainly Caucasian populations, but this did not reflect the general clinical practice of other hospitals. On the other hand, all the participating hospitals had a cath‐lab and this fact could be related to more invasive hospital management of ACS patients. The selection of the patients included in the registry was based on the diagnosis of ACS at discharge, therefore those patients with ACS who died during admission were not included. This might influence the mean scores of ischaemic and bleeding scales (GRACE and CRUSADE) used, since patients who died during ACS probably were patients with a higher risk profile. However, this is a prospective registry of real‐world ACS management that included consecutive patients, avoiding possible losses and biases. Moreover, there were no changes in clinical practice regarding to the management of ACS patients included in the registry due the voluntary nature of the ACHILLES registry. This voluntary attitude of the registry guarantees very high data quality, which was corroborated by external and independent audit. For all these reasons, the results should not be considered as a precise measure of treatment effect.
6. CONCLUSIONS
In this prospective, observational and current clinical practice ACS registry, the use of the novel P2Y12 inhibitors prasugrel and ticagrelor was more effective in the reduction of adverse events compared with clopidogrel in patients with ACS. Novel P2Y12 inhibitors prescription at discharge was independently associated with lower all‐cause mortality and MACE without differences in bleeding events. Clopidogrel remained the most common P2Y12 inhibitor employed for ACS, especially in older and high‐risk patients.
COMPETING INTERESTS
There are no competing interests to declare.
CONTRIBUTORS
J.M.R.N., M.A.E.P., J.M.R.C.and F.M.acquired the data, performed statistical analyses and drafted the manuscript. J.M.R.N and F.M.conceived and designed the research, drafted the manuscript and made critical revision. M.S., T.L., N.V.I., E.O.P., M.J.M., V.P, L.C., E.C., A.V., A.T.M.and J.G.M.M.acquired the data and made critical revisions. All authors gave final approval of the manuscript.
Supporting information
Supporting Information TableS1: Clinical factors related to all‐cause mortality by univariate and multivariate Cox regression analysis
Supporting Information TableS2: Clinical factors related to major adverse clinical events by univariate and multivariate Cox regression analysis
Supporting Information TableS3: Clinical factors related to major bleeding Bleeding Academic Research Consortium 3‐5 by univariate and multivariate Cox regression analysis
Supporting Information TableS4: Clinical factors related to major bleeding Bleeding Academic Research Consortium 2‐5 by univariate and multivariate Cox regression analysis
Supporting Information Fig.S1:Flow chart of patients
Supporting Information Fig.S2: Cox graph model for adverse events in diabetic patients according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC, Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event; TIMI,
Supporting Information Fig.S3: Cox graph model for adverse events in STEMI according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC: Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event; TIMI,
Supporting Information Fig.S4: Cox graph model for adverse events in NSTE‐ACS according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC, Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event TIMI,
Supporting Information Fig.S5. Event‐free survival curves for major bleeding and any bleeding events according to the PRECISE dual antiplatelet therapy risk score
ACKNOWLEDGEMENTS
This study was partially supported by a Research Grant from the Spanish Society of Cardiology (SEC).
Ruiz‐Nodar JM, Esteve‐Pastor MA, Rivera‐Caravaca JM, etal. One‐year efficacy and safety of prasugrel and ticagrelor in patients with acute coronary syndromes: Results from a prospective and multicentre ACHILLES registry. Br J Clin Pharmacol. 2020;86 1052–1061. 10.1111/bcp.14213
The authors confirm that the Principal Investigator for this paper is J.M.R.‐N.
All patients included in the ACHILLES registry, 1717 patients, provided individual signed informed consent and an external independent audit of the registry data (independent clinical research organization) was performed evaluating the correct inclusion of the patients, data analysed, compliance with the ethical principles and the presence of all signed informed consent of the patients included.
DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of thisstudy are available within the article and its supporting materials.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information TableS1: Clinical factors related to all‐cause mortality by univariate and multivariate Cox regression analysis
Supporting Information TableS2: Clinical factors related to major adverse clinical events by univariate and multivariate Cox regression analysis
Supporting Information TableS3: Clinical factors related to major bleeding Bleeding Academic Research Consortium 3‐5 by univariate and multivariate Cox regression analysis
Supporting Information TableS4: Clinical factors related to major bleeding Bleeding Academic Research Consortium 2‐5 by univariate and multivariate Cox regression analysis
Supporting Information Fig.S1:Flow chart of patients
Supporting Information Fig.S2: Cox graph model for adverse events in diabetic patients according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC, Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event; TIMI,
Supporting Information Fig.S3: Cox graph model for adverse events in STEMI according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC: Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event; TIMI,
Supporting Information Fig.S4: Cox graph model for adverse events in NSTE‐ACS according to the effect of clopidogrel or novel P2Y12 inhibitors. BARC, Bleeding Academic Research Consortium; HR, hazard ratio; MACE, major adverse cardiovascular event TIMI,
Supporting Information Fig.S5. Event‐free survival curves for major bleeding and any bleeding events according to the PRECISE dual antiplatelet therapy risk score
Data Availability Statement
The authors confirm that the data supporting the findings of thisstudy are available within the article and its supporting materials.