Abstract
Background:
Current clinical guidelines of acute coronary syndromes (ACS) recommend the use of potent antiplatelet therapy, prasugrel or ticagrelor, because both drugs consistently reduce cardiovascular events.
Purpose:
The aim of this study was to examine temporal changes in the use of optimal antiplatelet therapy in patients with ACS.
Methods:
A total of 1717 consecutive patients admitted for ACS in 3 tertiary hospitals from February 2014 to December 2015 were enrolled. We divided these 23 months into 4 semesters: period I (0-5 months), period II (6-11 months), period III (12-17 months), and period IV (17-23 months). Demographic, clinical, and treatment data were collected both at admission and at discharge.
Results:
Treatment with clopidogrel remained constant throughout the periods (52%, 50%, 44%, and 50% for periods I, II, III, and IV, respectively), whereas a progressive increase in ticagrelor treatment was observed (15%, 25%, 26%, and 28%; P = .001). Indeed, new P2Y12 agents showed an increase from 47% at the first semester to 65% in patients with ST-segment elevation myocardial infarction (STEMI), and in patients younger than 75 years from 36% to 53%. However, for patients older than 75 years, diabetic, and patients with end-stage kidney disease, clopidogrel was the second most commonly used antiplatelet agent.
Conclusion:
In this real-life registry of patients with ACS, we observed there is still a high rate of use of clopidogrel, despite guidelines recommendations, and our analyses also showed a trend toward the use of ticagrelor. Patients who received new antiplatelet agents were patients with STEMI, younger than 75 years, and with less comorbidities. However, the use of ticagrelor and prasugrel remains low, highlighting a therapeutic inertia with considerable gap between evidence-based clinical guidelines and daily clinical practice.
Introduction
Acute coronary syndrome (ACS) is a common and costly cause of hospital admission with high morbidity and mortality. 1 Platelet activation plays a pivotal role in the pathophysiology of development of ACS, thus antiplatelet therapy is the cornerstone of treatment to prevent thrombotic events in these patients.
Despite the proved efficacy of clopidogrel in treatment of ACS in several clinical trials and real-life, this antiplatelet drug has several limitations. Clopidogrel has low bioavailability, relative slower onset of action, and variability in patient responsiveness; approximately 15% to 30% of patients have been reported to be nonresponsive 2 and with suboptimal platelet inhibition. 3 New potent P2Y12 antiplatelet agents prasugrel and ticagrelor have been developed. Both new antiplatelet agents allow faster onset–offset and more predictable antiplatelet effect than clopidogrel. 4 Moreover, prasugrel and ticagrelor were associated with significantly reduced rates of ischemic events and cardiovascular deaths in patients with ACS, although with an increase in bleeding risk. 5,6
Current clinical guidelines of myocardial revascularization and ACS guidelines of European Society of Cardiology and American College of Cardiology/American Heart Association recommend early initiation and long-term maintenance of these new potent antiplatelet drugs (ticagrelor or prasugrel) for 12 months with high level of evidence (class I, level of evidence A or B). 7 –11
Although there is strong evidence that antiplatelet therapy reduces mortality and cardiovascular events in patients with ACS, data from real-world ACS registries 12 show a “risk-treatment paradox,” 13 where patients in the highest risk categories, such as diabetic patients, older patients, or patients with chronic kidney disease (CKD), are the least likely to receive the best and powerful evidence-based medical treatments.
Although previous observational registries have analyzed the real-life adherence to clinical guidelines in patients with ACS, 12,14,15 prospective available data in real-life from appropriate use of new P2Y12 are scarce. 16 For that reason, the aim of this study was to examine the clinical profile and temporal changes in use of optimal antiplatelet therapy in patients with ACS.
Methods
Study Design: The ACHILLES Registry
The ACHILLES registry (Spanish acronym from AntiagregaCión en HospItaLes del Levante ESpañol) is a multicenter, prospective, and observational study to know the management and antiplatelet therapy of all patients discharged due to definitive diagnosis of ACS. Three centers in south-eastern Spain enrolled patients from February 2014 to December 2015. We divided the period of 23 months into 4 semesters. The main objective of this registry was to assess the management and evolution of antiplatelet therapy in patients with ACS.
The ACHILLES registry assessed demographic characteristics, medical history, presenting symptoms, biochemical findings, risk factors, ischemic and bleeding risk scores (GRACE and CRUSADE), previous atherothrombotic events, prior anticoagulant and antiplatelet treatment, ACS treatment at admission and hospital discharge, echocardiography and coronary angiography findings, adverse events, adherence to antiplatelet therapy, reasons for discontinuation of antiplatelet treatment, cardiovascular mortality, all-cause mortality, MACE (the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke/transient ischemic attack), and bleeding events according to Bleeding Academic Research Consortium classified bleeding. 17 The information of antithrombotic and antiplatelet treatment was collected at admission, during hospitalization, and at discharge.
The baseline and follow-up visits of each patient were performed as follows: face-to-face visit at discharge; telephone contact by qualified personal or face-to-face follow-up at 3, 9, 12, and 18 months of the enrolment period. In this article, we only include the results of clinical management and treatment at discharge because the complete follow-up is ongoing.
Patient Selection
All consecutive patients older than 18 years discharged from hospital with any form of ACS were enrolled. Exclusion criteria included patients with ACS during another disease (type 2 acute myocardial infarction) such as stroke, severe anemia, hypoxemia, or sepsis. Also, patients who died during hospitalization period for ACS and patients who refused informed consent were excluded.
The study was conducted according to the ethical principles of Declaration of Helsinki and Good Clinical Practice Guidelines. In addition, it was approved by the clinical research ethics committees of the 3 hospitals and accepted 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). All participants provided signed informed consent. Moreover, an external audit of the registry data was performed by independent Clinical Research Organization in all participating hospitals to assess correct inclusion of patients, the compliance of ethical principles, and the possible existence of patients not included during the recruitment period. The ACHILLES is a voluntary registry, and all researchers only collected data with the patient’s discharge, without any influence on diagnostic or therapeutic decisions.
Definitions
ST-elevation myocardial infarction (STEMI) was diagnosed by the presence of the following criteria: persistence of acute chest pain ≥20 minutes and (1) ST-segment elevation of 1 mm in ≥2 standard leads, (2) ≥2 mm in ≥2 contiguous precordial leads, or (3) the presence of a left bundle branch block. 9,10
The clinical spectrum of non-ST-segment elevation ACS (NSTE-ACS) may be wider: Patients with acute chest pain and transient ST-segment elevation, persistent or transient ST-segment depression, T-wave inversion, flat T waves or pseudonormalization of T waves, or the electrocardiogram may be normal. The NSTE-ACS can be further subdivided based on cardiac biomarkers of necrosis (eg, cardiac troponin). If cardiac biomarkers are elevated and the clinical context is appropriate, the patient is considered to have NSTEMI; otherwise, the patient is deemed to have unstable angina (UA). 8,11
Statistical Methods
Categorical variables are expressed as frequencies with percentages. We tested normal distribution of continuous variables with the Kolmogorov-Smirnov test. The continuous variables normally distributed were expressed as mean (standard deviation), while those nonparametrically distributed variables were expressed as median with interquartile range. All variables and clinical parameters were examined by descriptive statistics. Comparison between groups was assessed by χ2 for categorical variables. Unpaired Student t-test was used to compare differences between parametric continuous variables and Mann-Whitey U test for nonparametric variables. Statistical significance was defined as a P value <.05. All statistical analyses were conducted using SPSS version 20.0 for Windows software program (SPSS Inc, Chicago, Illinois).
Results
Between February 2014 and December 2015, a total of 1853 consecutive patients with ACS undergoing hospital admission were included in the ACHILLES registry. Of these, 130 patients died during hospitalization period. We also excluded 6 patients who refused informed consent. Finally, we analyzed 1717 patients included in ACHILLES registry. We divided temporal period into 4 semesters: first semester from months 1 to 5, second semester from months 6 to 11, third semester from months 12 to 17, and fourth semester from months 18 to 23.
Global baseline data divided by semesters are shown in Table 1. Median age of ACHILLES registry was 67 (56-77) years. Patients more often had cardiovascular comorbidities, such as hypertension in 1159 (67.5%) patients, dyslipidemia in 1025 (59.7%) patients, and diabetes mellitus in 653 (38.0%) patients. The main type of ACS was NSTEMI in 750 (43.7%) patients, followed by STEMI in 574 (33.4%) patients and UA in 393 (22.9%) patients. No statistically significant differences in baseline characteristics were observed throughout the 4 semesters.
Basal Demographic and Clinical Characteristics of Global Population and Divided by Semesters.a
Abbreviations: STEMI, ST-elevation myocardial infarction; N-STEMI, non-ST-elevation myocardial infarction; ACE inhibitor, angiotensin-converting enzyme inhibitor; ARBs, angiotensin receptor blockers.
aData are presented as observed number (no) and percentage (%), mean (standard deviation), or median (interquartile range).
Temporal trends in the use of antiplatelet therapy for ACS are shown in Figure 1. The use of acetylsalicylic acid, statins, β-blocker, or angiotensin-converting enzyme inhibitor (ACE inhibitor)/angiotensin receptor blockers (ARBs) were similar between the 4 semesters. At hospital discharge, the use of clopidogrel remained constant throughout the 4 periods (52%, 50%, 44%, and 50%, from periods I to IV, respectively). For new antiplatelet agents, ticagrelor showed a linear increase from 15% at the first semester to 28% at the fourth semester; however, the rate of use of prasugrel was stable around 12%.
Temporal trends in antiplatelet therapy of patients with ACS divided by semesters at hospital discharge. ASA indicates acetylsalicylic acid.
Differences Between Types of ACS
Patients with NSTE-ACS were older (69 [59-78] vs 61 [53-72] years) and had more comorbidities, such as hypertension (70.3% vs 56.6%), dyslipidemia (62.7% vs 52.5%), and diabetes mellitus (41.0% vs 28.1%) although with lower GRACE score (126 [100-155] vs 152 [126-179]) and higher CRUSADE score (30 [19-41] vs 24 [16-35]) than patients with STEMI.
Figure 2A shows the temporal trends in the use of antiplatelet treatment in patients with STEMI and NSTE-ACS (UA and NSTEMI). Increase in new antiplatelet agents was observed, especially for ticagrelor. In patients with STEMI, we observed an important increase in the use of both prasugrel and ticagrelor from 47% at the first semester to 65% (P < .001), with a decrease in use of clopidogrel from 53% to 31% at the fourth semester (P < .001). Regarding patients with NSTE-ACS, we also observed an increase, especially in use of ticagrelor at the fourth semester (P < .007), with maintenance of the use of clopidogrel and low rate of use of prasugrel in this group.
A, Differences in temporal trends in antiplatelet therapy between patients with STEMI and patients with NSTE-ACS divided by semesters at hospital discharge. B, Differences in temporal trends in antiplatelet therapy of diabetic patients divided by semesters at hospital discharge. C, Differences in temporal trends in antiplatelet therapy of patients younger and older than 75 years divided by semesters at hospital discharge. ASA indicates acetylsalicylic acid; STEM, ST-elevation myocardial infarction; NSTE-ACS, non-ST-elevation acute coronary syndrome.
Differences in Antiplatelet Treatment Regarding Cardiovascular Comorbidities
Diabetic patients were older than general population (70 [61-78] vs 67 [56-77]) with more cardiovascular comorbidities such as hypertension (81.1% vs 67.5%), dyslipidemia (73.3% vs 59.7%), and had higher GRACE (141 [114-167] vs 135 [107-164]) and CRUSADE (36 [25-49] vs 28 [18-40]) scores.
Figure 2B shows the temporal trends in antiplatelet therapy of diabetic patients with ACS. We observed a significant increase in new antiplatelet drugs from 21% at the first semester to 39% at the fourth semester (P < .001). However, clopidogrel use remained the second most widely used antiplatelet drug in diabetic patients. The use of aspirin, statins, β-blocker, or ACE inhibitor/ARBs were similar between the 4 semesters.
Another interesting group are patients with CKD. Patients with severe impairment of renal function (glomerular filtration rate [GFR] <30 mL/min) were older (77 [69-85] vs 69 [59-77] years) and had higher rates of cardiovascular risk factors such as hypertension (93.7% vs 59.8%), dyslipidemia (71.4% vs 57.5%), or diabetes mellitus (58.7% vs 32.9%) than patients with GFR 60 to 90 mL/min. A significant lack of use of new potent antiplatelet drugs was observed in severe impaired renal function group (GFR <30 mL/min), whereas in the group of GFR 60 to 90 mL/min, the rate of use of new antiplatelet drugs increased from 34% to 52%.
Temporal Trends in the Use of Guideline-Recommended Therapies According to Age
Patients older than 75 years had more comorbidities, such as hypertension (82.4% vs 59.2%), dyslipidemia (62.6% vs 57.9%), and diabetes mellitus (43.7% vs 33.8%). Furthermore, patients older than 75 years showed both more ischemic risk assessed by GRACE score (165 [143-191] vs 123 [99-146]; P < .001) and bleeding risk by CRUSADE (40 [30-50] vs 23 [15-32]; P < .001) score.
Figure 2C shows temporal changes in use of antiplatelet treatment according to the age in patients with ACS. In patients younger than 75 years, the use of new antiplatelet agents managed to overcome the use of clopidogrel. In the fourth semester, ticagrelor was used in 40% of patients, prasugrel in 13% of patients with ACS, while clopidogrel only in 36% of patients (P < .001). However, in patients older than 75 years, clopidogrel was the second most commonly used antiplatelet agent while the use of prasugrel was nonexistent (P = .235).
Discussion
In this real-life registry of patients with ACS, we observed there is still a high rate of use of clopidogrel, despite guidelines recommendations, and our analyses also showed a trend toward the use of ticagrelor. However, the use of these drugs remains low, highlighting a considerable gap between evidence-based clinical guidelines and daily clinical practice. Patients who received clopidogrel had different baseline characteristics than patients with new antiplatelet agents group who were younger, have less comorbidities, and are more likely to present with STEMI.
Current clinical guidelines recommend the use of ticagrelor and prasugrel with high level of evidence for patients with ACS, both patients with STEMI and NSTE-ACS. 8,9,10,11 In our population, a marked decline in use of clopidogrel was observed in patients with STEMI with high rate of use of prasugrel and ticagrelor, above 65% on the fourth semester.
Nevertheless, for patients with NSTE-ACS, clopidogrel remained the second most commonly used antiplatelet therapy, with an increase in use of new P2Y12 agents only 11% throughout the registry. Prasugrel has shown good results in diabetic patients with ACS. However, the use of ticagrelor is widespread because it may be used in diabetic patients, elderly patients, and patients with renal disease and with previous stroke. The wide range of patients facilitates the use of ticagrelor by physicians in daily clinical practice and may justify the low use of prasugrel in our registry.
These results confirm previous registries. In GReekAntiPlatElet registry, 16 the use of clopidogrel was 36.4%, ticagrelor in 38.7%, and prasugrel in 24.7% for patients with STEMI/NSTE-ACS. Patients with STEMI had higher risk of acute death (high GRACE score), but patients with NSTE-ACS were older and had higher comorbidities with long-term risk of mortality. For this reason, patients with NSTE-ACS also required the use of potent antiplatelet drugs, but only 32.0% of our patients with NSTE-ACS received optimal therapy at discharge. Likewise, the Italian registry Eyeshot (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) 18 showed that 59.5% of patients with STEMI were treated with new antiplatelet agents and 33.9% of patients with NSTEMI, highlighting the gap between clinical guidelines and daily clinical practice. Moreover, the AntiPlatelet Treatment Observational Registries 19 also evaluated optimal secondary prevention therapy in patients with ACS in 14 European countries and showed that only 43% of patients received optimal therapy, particularly lack of optimal adherence related to dual-antiplatelet therapy.
Clinical inertia has been suggested as 1 possible reason for the underutilization of new antiplatelet agents according to the incapability to change established habits and routines. This term includes the inability to keep up to date with volume of information, problems with accessibility to the latest clinical guidelines, or difficulty in interpretation of this evidence. 20 Patient’s factors including cost issues related to ability to pay for treatment or issues related to the complexity of dose regimen may also contribute to antiplatelet agent underutilization. 21 Additionally, subjective underestimation of patient risk status by physicians entails a suboptimal adherence to current evidence and reduces the use of new P2Y12 drugs in patients in whom these agents are suitable. 13,21 To solve this problem, the real risk of each patient with ACS should be adequately known. However, East Asian populations demonstrate increased levels of platelet reactivity with high risk of ischemic and bleeding events. Large randomized clinical trials of prasugrel and ticagrelor in East Asian patients confirm that potent P2Y12 inhibitors agents can provide clinical benefit over clopidogrel in reducing risk from serious bleeding. 22 These findings may be the beginning of the road toward common treatment protocols with the latest evidence of therapeutic benefit of prasugrel and ticagrelor to facilitate the understanding and adherence of physicians to these agents.
One of the main responsibilities of Scientific Societies is to identify the main problems that hinder the optimal care of ACS. On the one hand, we should emphasize the knowledge of evidence-based recommendations to clinical physicians and health services. On the other hand, health services should limit treatment cost to the patient. Unfortunately, different reimbursement systems are the main barriers that favor therapeutic inertia and global inequalities in access to optimal health care.
This therapeutic inertia is especially evident in older patients. Our data revealed ticagrelor was the most commonly used novel antiplatelet agent, whereas the use of prasugrel was nonexistent in patients older than 75 years. Ticagrelor was used predominantly in patients with STEMI and diabetic patients, whereas prasugrel was used in patients with STEMI and those younger than 75 years. Likewise, our prospective observational data are consistent with Antithrombotic Therapy in patients with Acute Coronary Syndrome registry 14 regarding the use of prasugrel in elderly patients with STEMI and Acute Myocardial Infarction in Switzerland registry, 23 which showed limited use of prasugrel in patients >75 years or <60 kg. As expected, we observed elderly patients had more comorbidities, previous cardiovascular events, and high GRACE and CRUSADE scores. Consequently, these patients had higher cardiovascular and bleeding outcomes during admission period and after discharge than younger patients with ACS. Some evidence suggests that worse outcomes in older patients were at least partially attributable to a decreased adherence to guideline-recommended therapies. 23 –25 For dual-antiplatelet therapy, clopidogrel was the second most commonly used antiplatelet agent in older patients with ACS, followed distantly by ticagrelor. Physicians still seemed to be reluctant to switch clopidogrel to ticagrelor in elderly patients, despite clinical guidelines recommendations 24 and the superiority of ticagrelor over clopidogrel in terms of efficacy as reported in the Platelet Inhibition and Patient Outcomes (PLATO) elderly subgroup. 26
Similar findings were observed in end-stage kidney disease, where clopidogrel was the main second antiplatelet drug (81%) in comparison to new antiplatelet drugs (12%), and the trend continued throughout the 4 semesters, without the use of prasugrel. Nonetheless, in patients with GFR 30 to 59 mL/min, we observed a small increase in the use of new antiplatelet agents (16%, 27%, 33%, and 15%), particularly ticagrelor. Renal dysfunction, even moderate CKD, is a powerful marker of risk in ACS, and renal patients have an extremely high rate of ischemic and bleeding events related to ACS. 27 In a subanalysis of PLATO in patients with GFR <60 mL/min and ACS, ticagrelor compared to clopidogrel significantly reduces ischemic endpoints and mortality without a significant increase in major bleeding. 28 Despite these, we observed physicians distrusted the use of new antiplatelet agents in patients with moderate and severe CKD.
In the same way, we observed lack of adherence to clinical guidelines in diabetic patients. Platelets of diabetic patients have been proven to be hyperreactive with intensified adhesion, activation, and aggregation. 29 Moreover, diabetic patients are more likely to have multivessel disease, more comorbidities, and increased risk of cardiovascular events in comparison to nondiabetic patients. 30 For this reason, potent platelet-inhibiting drugs in diabetic patients are needed to avoid clinical outcomes. Our data showed diabetic patients with ACS were older and have more comorbidities and risk scores (GRACE and CRUSADE) than global population. Previous studies have shown that patients with ACS having diabetes tend to be managed more conservatively and are less likely to receive evidence-based therapies, despite the evidence that they would derive similar or even greater benefits from aggressive treatment. 31 Despite the encouraging findings in diabetic patients in TRITON-TIMI 38 trial with prasugrel, 5 we only observed 15% of patients treated with prasugrel and that percentage is maintained throughout the semesters. In addition, we observed an increase in treatment with ticagrelor from 6% to 24%. Nevertheless, in real-life, high-risk patients with ACS like diabetic patients are managed less aggressively than low-risk patients with ACS.
Study Limitations
The primary limitation of this study is its nonrandomized and observational nature of ACS registry. Although registries represent better daily clinical practice than clinical trials, the population may be very heterogeneous and limit the generalizability about 1 therapeutic approach. Indeed, we evaluated only patients with ACS admitted to 3 south-eastern Spanish hospitals during the analysis period, so a selection bias related to the unequal geographic distribution of participating hospital may have influenced these results. Another limitation is related to inclusion criteria. The selection of patients included in ACHILLES registry was based on discharge diagnosis of ACS; therefore, we did not include patients admitted with ACS who died during hospitalization period. This could influence the overall calculation of risk scores (GRACE and CRUSADE) because patients usually die from ACS trend to be higher cardiovascular risk profile.
In terms of strengths, our results come from a relatively large cohort of all consecutive patients enrolled in a prospective registry at discharge, avoiding potential loss of patients, to reflect contemporary practices in the management of ACS in the “real world.” This voluntariness of patients included in ACHILLES registry guarantees a very high quality of the data that has been corroborated by an external and independent audit.
Conclusion
In this prospective real-life registry of patients with ACS, we observed there is still a high rate of use of clopidogrel, despite guidelines recommendations, and our analyses also showed a trend toward the use of ticagrelor. Patients who received new antiplatelet agents were younger, with less comorbidities, and were more likely to present with STEMI. However, the use of ticagrelor and prasugrel remains low, highlighting a therapeutic inertia with considerable gap between evidence-based clinical guidelines and daily clinical practice.
Footnotes
Authors’ Note
Ethical Approval: All procedures performed in this prospective study that involve human participants was conducted according the ethical standards of the institutional ethical committee of each hospital and with the 1964 Helsinki Declaration and its later amendments and Good Clinical Practice Guidelines. Informed consent was obtained from all individual participants included in this study.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JM Ruiz-Nodar has received research grants and speaker fees from Medtronic, Boston Scientific, and Astrazeneca. M Valdés has received research grants and speaker fees from Medtronic and Boston Scientific. A Tello has received research grants from Amgen, AstraZeneca, Merk, Ferrer Pharma, and Daiichi-Sankyo. F Marín has received funding for research, consultancy, and lecturing from Boston Scienficis, Bayer, AstraZeneca, Daiichi-Sankyo, and Boehringer Ingelheim. The rest of authors report no conflicts of interest.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study has been partially supported by a research grant from the Spanish Society of Cardiology (SEC-Project of Clinical Research in Cardiology Dr Pedro Zarco 2016).
