Author + information
- Received April 15, 2016
- Revision received April 28, 2016
- Accepted May 3, 2016
- Published online September 13, 2016.
- Dimitrios Alexopoulos, MDa,b,∗ ( )(, )
- Ioanna Xanthopoulou, MDa,
- Athanasios Moulias, MDa and
- John Lekakis, MDb
- aDepartment of Cardiology, Patras University Hospital, Patras, Greece
- bDepartment of Cardiology, Attikon University Hospital, Athens, Greece
- ↵∗Reprint requests and correspondence:
Dr. Dimitrios Alexopoulos, Cardiology Department, Attikon University Hospital, Athens 12462, Greece.
Physicians considering prescription of P2Y12-receptor antagonist for long-term (>1 year) protection of patients post-myocardial infarction face the trilemma of selecting between clopidogrel, prasugrel, or ticagrelor. Differential ischemic benefits derived from relevant trials may assist in tailoring treatment, although the different bleeding definitions applied make any meaningful comparison of each agent’s bleeding potential very difficult. Considering the available data and recognizing the significant limitation of observations obtained thus far from subgroup analyses, prasugrel appears to provide higher anti-ischemic protection than clopidogrel. Ticagrelor seems to be an attractive option for patients with renal dysfunction, peripheral arterial disease, or following a brief P2Y12-receptor antagonist interruption, whereas clopidogrel may be advised in the presence of cost and availability issues. As head-to-head comparative trials between P2Y12-receptor antagonists are lacking, selection of a specific agent by the clinician should be made on the basis of critical appraisal of available large clinical datasets.
Dual antiplatelet treatment with a P2Y12-receptor antagonist in addition to aspirin for 1 year is considered mandatory in most patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI) with stent implantation (1–4). Based mainly on the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) and PLATO (PLATelet inhibition and patient Outcomes) trial results (5,6), and despite increased bleeding potential and cost, prasugrel and ticagrelor are preferentially suggested for use over clopidogrel, unless contraindications/special warnings and precautions exist (1,3,4,7). Moreover, adverse events, availability, cost, adherence to treatment, and local reimbursement policies are among the factors that significantly influence selection of specific agents when prescribing P2Y12-receptor antagonists (8). During the acute phase of ACS (in the pre-hospital setting or during hospitalization), at discharge or post-discharge, and during the recommended 1-year period of P2Y12-receptor antagonist administration, the practicing physician commonly faces the dilemma of the choice to prescribe either a novel agent or clopidogrel, or even a trilemma choice between clopidogrel, prasugrel, or ticagrelor. Of note, there is only a weak proposal for extending P2Y12-receptor antagonist administration beyond 1 year (Class IIb, Level of Evidence: A), and only after careful assessment of the patient’s ischemic and bleeding risks (3,4). Following the accrual of recent data, the potential beneficial role of prolonged P2Y12-receptor antagonist use beyond the first year has emerged and been re-emphasized.
The purpose of this review was to analyze the available data for the use of P2Y12-receptor antagonists for long-term protection of post-myocardial infarction (MI) patients in an effort to provide practical guidance for the clinician in selecting between clopidogrel, prasugrel, or ticagrelor.
Increased Long-Term Risk in Patients With a History of MI
It has been well appreciated that patients with prior ACS are at heightened risk for recurrent ischemic events beyond the first year after the index event. In the GRACE (Global Registry of Acute Coronary Events) long-term study, 3,721 ACS patients were prospectively recruited and followed for a median period of 5 years; death occurred post discharge in 19% of ST-segment elevation myocardial infarction (STEMI) and 22% of non–ST-segment elevation myocardial infarction (NSTEMI) patients, uncovering an under-recognized substantial late mortality, particularly in the NSTEMI ACS cohort (9). A preliminary report of 140,887 1-year post-MI survivors drawn from unselected electronic health and administrative records in Sweden, the United States, England, and France showed the risk of further MI, stroke, or death remained high (approximately 1 in 5) across the 3 years and 4 countries studied, with fairly constant annual risks (10). More recently, in a retrospective cohort study of 97,254 MI patients who were alive 1 week after discharge, patients without a combined endpoint event (nonfatal MI, nonfatal stroke, or cardiovascular death) during the first 365 days carried a composite endpoint risk of 20.0% in the following 36 months (11). This heightened late risk of ischemic events emphasizes the need for prolonged surveillance and intensive secondary prevention efforts. Of importance, the 3-year cumulative risk of hospitalized bleeding events also remains high, although with significant between-country variations (10).
Impact of Long-Term P2Y12-Receptor Antagonists in Post-MI Patients
Long-term use of P2Y12-receptor antagonists in patients with prior MI has been studied in 3 major trials (Tables 1, 2, and 3). In the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, clopidogrel, 75 mg once daily (o.d.), was compared to placebo, added to low-dose aspirin therapy in a stable population with either established atherothrombotic disease or multiple risk factors for atherothrombotic events. No statistically significant benefit was found with clopidogrel in the overall population studied. However, in patients with documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease (PAD) and over a follow-up period of 27.6 months, clopidogrel provided a lower rate (7.3%) of the primary efficacy endpoint (a composite of cardiovascular death, MI, or stroke) than placebo (8.8%), with a hazard ratio (HR) of 0.83 (95% confidence interval [CI]: 0.72 to 0.96; p = 0.01) (12). Moderate bleeding was significantly increased with clopidogrel: 2.0% versus 1.3% (HR: 1.60; 95% CI: 1.16 to 2.20; p = 0.004). In a post hoc subgroup analysis of 3,846 patients with a history of MI (at a median time of 23.6 months earlier), the primary efficacy endpoint rates were 6.6% and 8.3% in the clopidogrel and placebo arms, respectively (HR: 0.774; 95% CI: 0.613 to 0.978; p = 0.031).
In the DAPT (Dual Antiplatelet Therapy) study, 9,961 patients who did not experience adverse events in the first year after PCI with drug-eluting stent(s) (DES) were randomized to receive an additional 18 months of a thienopyridine therapy (clopidogrel, 75 mg o.d., or prasugrel, 10 mg o.d. [5 mg o.d. if <60 kg in weight]) or placebo in addition to aspirin, 75 to 162 mg o.d. (13). Continued treatment with a thienopyridine compared with placebo reduced the rates of both stent thrombosis, 0.4% versus 1.4%, respectively (HR: 0.29; 95% CI: 0.17 to 0.48: p < 0.001), and major adverse cardiovascular and cerebrovascular events (MACCE: a composite of death, myocardial infarction, or stroke), 4.3% versus 5.9%, respectively (HR: 0.71; 95% CI: 0.59 to 0.85; p < 0.001). The rate of moderate or severe bleeding, as assessed according to GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) criteria, was increased with continued thienopyridine treatment: 2.5% versus 1.6%, respectively (HR: 1.61; 95% CI: 1.21 to 2.16; p = 0.001). Among 11,648 DAPT patients treated with either DES or bare-metal stents, 3,576 patients (30.7%) presented with MI as the index event 1 year prior to randomization (14). In this cohort, continued thienopyridine therapy for between 12 and 30 months reduced stent thrombosis compared with placebo: 0.5% versus 1.9%, respectively (HR: 0.27; 95% CI: 0.13 to 0.57; p < 0.001). This effect was consistent in both the MI and non-MI cohorts (p interaction = 0.69). In the MI cohort, the MACCE rate was reduced with continued thienopyridine therapy for between 12 and 30 months, from 6.8% in the placebo group to 3.9% in the active treatment group (HR: 0.56; 95% CI: 0.42 to 0.76; p < 0.001). The reduction in MACCE was greater for patients with MI than for those in the non-MI cohort (p interaction = 0.03). Moderate or severe bleeding was higher for continued thienopyridine therapy (1.9%) than with placebo (0.8%; HR: 2.38; 95% CI: 1.27 to 4.43; p = 0.005), and this effect was consistent across patients with and without MI presentation (p interaction = 0.21).
In the PEGASUS–TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial, 21,162 participating patients with prior MI 1 to 3 years earlier were randomized to receive ticagrelor at a dosage of 90 mg twice daily, ticagrelor at a dosage of 60 mg twice daily, or placebo in addition to aspirin, 75 to 150 mg o.d. (15). At a median follow-up of 33 months, the composite of cardiovascular death, MI, or stroke was reduced (HR: 0.84; 95% CI: 0.76 to 0.94; p = 0.001 for pooled ticagrelor dosages; HR: 0.85; 95% CI: 0.75 to 0.96; p = 0.008 for 90 mg of ticagrelor; and HR: 0.84; 95% CI: 0.74 to 0.95; p = 0.004 for 60 mg of ticagrelor vs. placebo). TIMI (Thrombolysis In Myocardial Infarction) major bleeding occurred more frequently with ticagrelor (2.60% with 90 mg of ticagrelor and 2.30% with 60 mg of ticagrelor) than with placebo (1.06%) with HR of 2.69 (95% CI: 1.96 to 3.70) and HR of 2.32 (95% CI: 1.68 to 3.21), respectively, and p value of <0.001 for each dose versus placebo. Cardiovascular mortality was 2.90% with ticagrelor (pooled doses) versus 3.39% with placebo (HR: 0.85; 95% CI: 0.71 to 1.00; p = 0.06). Contrary to the PLATO findings, where use of ticagrelor (vs. clopidogrel) was followed by a higher rate of intracranial hemorrhage, no such difference was found among the 3 PEGASUS–TIMI 54 groups. Although both of the ticagrelor doses were associated with a similar magnitude of efficacy, the 60-mg dose was associated with numerically less bleeding and dyspnea and a lower rate of discontinuation than the 90-mg dose, implying a more attractive benefit–risk profile. The U.S. Food and Drug Administration recently approved a dosage of 60 mg twice daily for ticagrelor (16).
In a meta-analysis of the 3 trials discussed previously, along with 3 other studies involving ACS patients, dual antiplatelet treatment beyond 1 year decreased the risk of MACCE (a composite of cardiovascular death, nonfatal MI, and nonfatal stroke) compared with aspirin alone (6.4% vs. 7.5%, respectively; risk ratio [RR]: 0.78; 95% CI: 0.67 to 0.90; p = 0.001) (17). Cardiovascular death was reduced (2.3% vs. 2.6%, respectively; RR: 0.85; 95% CI: 0.74 to 0.98; p = 0.03), whereas noncardiovascular mortality did not differ significantly (RR: 1.03; 95% CI: 0.86 to 1.23; p = 0.76). The risk of major bleeding was increased (1.85% vs. 1.09%, respectively; RR: 1.73; 95% CI: 1.19 to 2.50; p = 0.004) but the risk of fatal bleeding was not (0.14% vs. 0.17%, respectively; RR: 0.91; 95% CI: 0.53 to 1.58; p = 0.75). Limitations of this meta-analysis (e.g., pooled trials with heterogeneous populations, no evaluation of individual patient-level data, analysis of subgroups) are recognized.
Taken together, the results from the randomized studies discussed previously and meta-analysis suggest that in patients with a prior MI and features of high ischemia and low bleeding risk, physicians may consider reinitiating or extending treatment with a P2Y12-receptor antagonist beyond 1 year.
Which P2Y12-Receptor Antagonist to use?
Physicians deciding on the use of long-term (>1 year) P2Y12-receptor antagonists are likely facing a trilemma: the choice between clopidogrel, 75 mg o.d. (used in CHARISMA and in 66.4% of patients in the MI cohort of DAPT); prasugrel, 10 mg o.d. or 5 mg o.d. for patients <60 kg (used in 33.6% of patients in the MI cohort of DAPT); or ticagrelor, 60 mg twice daily (used in one-half of the PEGASUS active comparator population) (Central Illustration). In fact, direct comparisons among the different P2Y12-receptor antagonists with respect to efficacy, safety, and cost effectiveness for the long-term treatment of post-MI patients do not exist, creating the challenge of comparing trials like CHARISMA, DAPT, and PEGASUS–TIMI 54.
The first, obvious question is the choice between clopidogrel or a more potent agent like prasugrel or ticagrelor. Absolute risk reductions in the composite of cardiovascular death, MI, or stroke (defined as MACCE in DAPT and MACE in PEGASUS–TIMI 54) were 1.7%, 2.9%, and 1.27% for clopidogrel, thienopyridine, and ticagrelor, 60 mg twice daily, in CHARISMA, DAPT, and PEGASUS–TIMI 54, respectively (Table 3, Figure 1). Absolute risk increase in GUSTO moderate bleeding was 0.7%, in GUSTO severe/moderate bleeding 1.1%, and in TIMI major bleeding 1.24% with clopidogrel, thienopyridine, and ticagrelor, 60 mg twice daily, in CHARISMA, DAPT, and PEGASUS, respectively (Table 3, Figure 2). Importantly, the time interval from the index event to randomization was 12 months in DAPT but 23.6 and 20.4 months in CHARISMA and PEGASUS–TIMI 54, respectively. Data from PEGASUS–TIMI 54 have convincingly shown a higher rate of MACCE in patients in the placebo arm who had discontinued their P2Y12-receptor antagonist within the previous 30 days (9.91% at 3 years) than that in those who had discontinued 30 days to 1 year previously (8.70%) and those who stopped more than 1 year before randomization (6.91%; p trend = 0.0097) (18). Therefore, patients studied in DAPT may be considered to have had a higher ischemia risk than those in CHARISMA or in PEGASUS–TIMI 54, as they were studied closer to their index event.
Clopidogrel is the most widely used P2Y12-receptor antagonist worldwide, available in generic form and with a lower bleeding potential (5,6). Nevertheless, clopidogrel carries the drawback of a variable response, with approximately one-third of Caucasian patients having inadequate platelet inhibition by criteria that have been developed mostly from studies in the acute setting of ACS or PCI (19). Of note, platelet function analysis was not used for treatment guidance in any of the long-term P2Y12-receptor antagonist post-MI studies and represents for this setting “navigation in unknown waters.” Although clopidogrel selection for cases without high on-clopidogrel platelet reactivity or categorized as rapid metabolizers by genetic testing may be attractive, it lacks supportive data and is absolutely speculative.
Regarding selection of clopidogrel versus prasugrel, some information is provided by the results of DAPT, in which the overall population treatment effect on MACCE was affected by the thienopyridine type, as prasugrel-treated patients had more benefit from extended treatment (continued prasugrel, 4.0% vs. placebo 7.3%; HR: 0.52; 95% CI: 0.38 to 0.71) than those treated with continued clopidogrel (4.5% vs. placebo, 5.2%; HR: 0.80; 95% CI: 0.64 to 1.01), p interaction = 0.03. However, in the MI cohort (14), the benefit from extended P2Y12-receptor antagonist treatment was consistent across the thienopyridine type: the definite or probable stent thrombosis rate was 0.4% in the clopidogrel group versus 1.2% in the placebo group (HR: 0.29; 95% CI: 0.10 to 0.90) and 0.9% in the prasugrel group versus 3.2% in the placebo groups (HR: 0.26; 95% CI: 0.10 to 0.69), with p interaction = 0.86. The MI rate was 2.3% in the clopidogrel versus 4.3% in the placebo group (HR: 0.52; 95% CI: 0.32 to 0.83) and 2.2% in the prasugrel versus 6.8% in the placebo group (HR: 0.32; 95% CI: 0.17 to 0.59), with p interaction = 0.22. Furthermore, the extended P2Y12-receptor antagonist treatment effects in GUSTO moderate or severe bleeding were consistent across thienopyridine type: 2.2% and 0.6% with clopidogrel and placebo, respectively (HR: 3.60; 95% CI: 1.56 to 8.29) and 1.4% and 1.2% with prasugrel and placebo, respectively (HR: 1.14; 95% CI: 0.41 to 3.15), with p interaction = 0.09.
Long-term protection post MI might require a lower intensity of platelet inhibition than in the acute setting, and therefore the role of a lower dosage of prasugrel (e.g., 5 mg o.d.) could be considered. However, data from the small cohort of DAPT patients receiving 5 mg of prasugrel have not been provided. Of note, in the elderly cohort of medically managed ACS patients (78.4% presenting with NSTEMI) treated with 5 mg of prasugrel, the cumulative risk of primary efficacy endpoint and non-coronary artery bypass graft-related TIMI major bleeding through 30 months were similar to those in the clopidogrel arm (20).
In PEGASUS–TIMI 54, active treatment was compared to placebo, and we cannot speculate about the relative efficacy and safety of a ticagrelor-based versus a clopidogrel-based strategy in a similar population. Of note, a pharmacodynamic comparison study between clopidogrel, 75 mg o.d., and ticagrelor, 60 mg twice daily, in the chronic phase of stable post-MI patients with PEGASUS–TIMI 54-like characteristics is currently underway (NCT02663713).
In an effort to individualize treatment duration, a post hoc analysis of the DAPT population has proposed a decision tool to identify whether an individual patient is more likely to derive benefit or harm from extension of dual antiplatelet therapy beyond 1 year after PCI (21). On the basis of a composite of individual patient characteristics and simultaneously accounting for patient risks of ischemia and bleeding events with continued therapy, a 9-item score was created, consisting of age (≥75 years of age, 65 to 74 years of age), prior PCI or MI, stent diameter <3 mm, congestive heart failure or left ventricular ejection fraction <30%, MI at presentation, paclitaxel-eluting stent, smoking, and diabetes. In patients with a DAPT score <2, continued thienopyridine therapy versus placebo was associated with no significant differences in stent thromboses or MI (1.7% vs. 2.3%, respectively; p = 0.07) and MACCE rates (3.7% vs. 3.8%, respectively; p = 0.73), whereas GUSTO moderate/severe bleeding occurred more frequently with continued thienopyridine (3.0%) than with placebo (1.4%; p < 0.001). In contrast, patients with a DAPT score ≥2 had a favorable benefit-risk ratio with continued thienopyridine compared with placebo: the stent thrombosis or MI rates were 2.7% and 5.7%, respectively (p < 0.001), whereas the MACCE rates were 4.9% and 7.6%, respectively (p < 0.001). GUSTO moderate/severe bleeding did not differ between the 2 treatment strategies (1.8% vs. 1.4%, respectively; p = 0.26). Recognized limitations of the DAPT score are that it is the product of a post hoc analysis, not powered to examine differences in outcomes between subgroups, and that incomplete information on potential unmeasured confounders cannot be excluded. A recent exploratory analysis of the DAPT study by MI status and DAPT score described, in patients with any MI and a score ≥2, a reduction in MI/stent thrombosis with continued thienopyridine versus placebo (2.7% vs. 6.0%, respectively; p < 0.001) and bleeding rates of 1.5% vs. 1.1%, respectively (p = 0.24) (22); the number needed to benefit was reduced from 39 to 31, and the number needed to harm was increased from 106 to 226. In contrast, among patients with DAPT scores <2, continued thienopyridine therapy was associated with increased bleeding (3.2% vs. 1.2%, respectively; p = 0.01) and no significant differences in ischemia rates.
Thus far, 2 pre-specified subanalyses of PEGASUS-TIMI 54 trial have likely contributed to the identification of subgroups that will derive the most benefit with long-term ticagrelor treatment. For MACCE, renal dysfunction did not modify ticagrelor’s effect (p interaction = 0.44) (23). However, the absolute risk reduction was 4 times higher in patients with renal dysfunction than in those without: 2.70% (95% CI: 0.49 to 4.93) versus 0.63% (95% CI: −0.32 to 1.57), respectively. These findings are in line with comparisons between ticagrelor and clopidogrel in the setting of ACS, where a 4-fold greater absolute risk reduction in MACCE was described in patients with renal dysfunction (24). TIMI major bleeding events were increased with ticagrelor to a similar degree in patients with or without renal dysfunction (p interaction = 0.38), whereas the absolute increase in TIMI major bleeding with ticagrelor did not differ according to renal dysfunction (1.19% vs. 1.43%, respectively). Patients with renal dysfunction appear, therefore, to be good candidates for long-term treatment with ticagrelor.
In another subanalysis of 18,761 patients (88.7% of the total PEGASUS–TIMI 54 population with a recorded history of the timing of their last P2Y12-receptor antagonist dose prior to randomization), results were reported for patients ≤30, >30 to 360, and >360 days from P2Y12-receptor antagonist withdrawal (18). Regarding MACCE, patients who restarted ticagrelor versus placebo within 30 days had more benefit compared with those who restarted at a later time (HR: 0.73; 95% CI: 0.61 to 0.87; p = 0.0005; HR: 0.86; 95% CI 0.71 to 1.04; p = 0.0853; and HR: 1.01; 95% CI: 0.80 to 1.27; p = 0.9249, respectively; p trend for interaction < 0.001). For the 7,181 patients (38%) who had their last dose within 30 days from randomization, the MACCE rate was 9.9% for placebo, 8.0% for the ticagrelor 60-mg arm (HR: 0.75; 95% CI: 0.61 to 0.92; p = 0.0064), and 7.4% for the ticagrelor 90-mg arm (HR: 0.70; 95% CI: 0.57 to 0.87; p = 0.0009). Both of the doses of ticagrelor increased TIMI major bleeding compared with placebo, regardless of time from the last dose of P2Y12-receptor antagonist (p interaction for 90 mg = 0.90; 0.62 for 60 mg). In the brief interruption group, the TIMI major bleeding rate was 0.74% in the placebo arm, 2.50% in the pooled doses (HR: 3.36; 95%CI: 1.91 to 5.92), 2.63% in the ticagrelor 60-mg arm (HR: 3.30; 95% CI: 1.80 to 6.03), and 2.36% in the ticagrelor 90-mg arm (HR: 3.44; 95% CI: 1.88 to 6.28; p < 0.0001 for all versus placebo). These results suggest that the benefit of ticagrelor depends significantly on the time from the last dose, being more marked in patients continuing on or restarting after only a brief interruption of P2Y12-receptor antagonism. Physicians may strongly consider no interruption or early reinitialization of treatment with ticagrelor, rather than late reinitialization of treatment in patients who were stable for more than 2 years from their MI and without P2Y12-receptor antagonist therapy for more than a year.
Moreover, in a PEGASUS–TIMI 54 subgroup analysis by the presence of PAD at baseline, no heterogeneity in the relative risk reduction with ticagrelor for MACCE was described (p interaction = 0.41); a greater absolute risk reduction was seen for patients with PAD (4.1%; 95% CI: −1.07% to 9.29%) than for those without (1.0%; 95% CI: 0.14% to 1.9%) (25). The ticagrelor-induced increase in TIMI major bleeding was consistent among groups (p interaction = 0.28). Patients with PAD may therefore represent another clinical scenario, where ticagrelor administration appears appealing.
Notably, a PEGASUS score analog to the DAPT score, which may assist in selection of the most beneficial long-term ticagrelor dose for the post-MI patient, has not yet been developed.
Prior Stenting and Type of Stent
In recent years and with the use of second-generation DES, very late stent thrombosis has become less of an issue, and events not related to the stent site appear to play the major role. In the overall population of DAPT, the rate of MI not related to stent thrombosis was 1.8% and 2.9% in the continued thienopyridine and placebo groups, respectively (HR: 0.59; 95% CI: 0.45 to 0.78; p<0.001), and accounted for 55% of the treatment benefit (13). The DES type appeared to have an impact on the benefit obtained from continued thienopyridine therapy on lower MACCE with second- versus first-generation stents (p interaction = 0.048). In PEGASUS–TIMI 54 and in 16,891 stented patients (51% bare metal stents; 49% DES) the majority of events at 3 years (91%) were non–stent-related, supporting the significance of extended dual antiplatelet treatment as a secondary prevention measure for the post-MI patient, regardless of stent implantation (26). Whether the choice of a P2Y12-receptor antagonist for the long-term treatment of the post-MI patient should be influenced by prior coronary stenting and the type of stent implanted has not been addressed thus far.
Studies in ACS patients undergoing PCI have shown a wider applicability of ticagrelor than prasugrel, mainly due to the relatively high prevalence of contraindications or warnings for the latter (e.g., history of stroke/transient ischemic attack, >75 years of age, weight <60 kg) (5,7,27). Nevertheless, ticagrelor is accompanied by a higher rate of dyspnea (6). In DAPT, the discontinuation rate of the study drug did not differ significantly between the continued thienopyridine and placebo arms (21.4% and 20.3%, respectively; p = 0.18). In contrast, in PEGASUS–TIMI 54, a higher proportion of patients receiving active treatment discontinued the study: 32.0%, 28.7%, and 21.4% in the 90-mg ticagrelor, 60-mg ticagrelor, and placebo groups, respectively (p < 0.001 for the comparison of each ticagrelor dose versus placebo). These differences were mainly caused by higher premature discontinuation rates in the 2 ticagrelor groups due to adverse events: 20.3%, 17.8%, and 11.1% in the 90-mg ticagrelor group, 60-mg ticagrelor group, and placebo group, respectively. The requirement for twice daily administration of ticagrelor might also affect the patient’s adherence to long-term treatment. Therefore, when considering the choice between prasugrel and ticagrelor, it seems that more patients are eligible for prescription of ticagrelor, although with the likelihood of a higher rate of discontinuation due to adverse events.
Finally, the cost of novel agents, availability of generic clopidogrel, and reimbursement policies are likely to affect the long-term antiplatelet therapy choice for the individual patient. Even if a clinical trial comparing clopidogrel, prasugrel, and ticagrelor were undertaken and led to favorable results for the novel agents, one might still be left with the economic forces that drive physician usage. Notably, despite PLATO showing a clear net clinical benefit of ticagrelor over clopidogrel, there is moderate uptake of ticagrelor in most parts of the world.
Physicians facing the trilemma of choice among P2Y12-receptor antagonists for long-term (>1 year) therapy of post-MI patients should mainly balance the anti-ischemic benefits obtained in trials of clopidogrel, prasugrel, and ticagrelor. Different bleeding definitions applied in different trials make any meaningful comparison of the relative bleeding potential of each agent practically impossible. Considering the available data, prasugrel appears to provide higher anti-ischemic protection than clopidogrel. Ticagrelor seems to be an attractive option for patients with renal dysfunction, PAD, or following brief P2Y12-receptor antagonist interruption. Clopidogrel may be advised in the presence of cost and availability issues. Of note, all relevant observations obtained so far have been on the basis of subgroup analyses. Prospectively designed and adequately powered clinical comparisons between P2Y12-receptor antagonists would be ideal to develop evidence-based recommendations on long-term antiplatelet treatment in post-MI patients. However, one would have to assume equipoise for a comparative study to be undertaken, and a head-to-head clinical trial is likely to require tens of thousands of patients, making it potentially prohibitively expensive. As it is unlikely that we will see such a study in the future, selection of a specific P2Y12-receptor antagonist by the clinician on the basis of the available clinical data appears to be a more pragmatic goal.
Dr. Alexopoulos has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Bayer, and The Medicines Company; and lecture honoraria from AstraZeneca. Dr. Lekakis has received advisory board fees and lecture honoraria from AstraZeneca, Actelion, and Merck Sharp and Dohme. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome
- drug-eluting stent(s)
- major adverse cardiovascular and cerebrovascular events
- myocardial infarction
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Received April 15, 2016.
- Revision received April 28, 2016.
- Accepted May 3, 2016.
- 2016 American College of Cardiology Foundation
- Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC),
- Steg P.G.,
- James S.K.,
- Atar D.,
- et al.
- O’Gara P.T.,
- Kushner F.G.,
- Ascheim D.D.,
- et al.
- Amsterdam E.A.,
- Wenger N.K.,
- Brindis R.G.,
- et al.
- Roffi M.,
- Patrono C.,
- Collet J.P.,
- et al.
- Alexopoulos D.,
- Goudevenos J.A.,
- Xanthopoulou I.,
- et al.,
- GRAPE Investigators
- Fox K.A.,
- Carruthers K.F.,
- Dunbar D.R.,
- et al.
- ↵Rapsomaniki E, Janzon M, Cohen DJ, et al. International comparison of outcomes among 140,887 survivors after acute myocardial infarction: real-world evidence from electronic health and administrative records. Paper presented at: European Society of Cardiology Congress; August 30–September 3, 2014; Barcelona, Spain.
- Jernberg T.,
- Hasvold P.,
- Henriksson M.,
- et al.
- Bhatt D.L.,
- Flather M.D.,
- Hacke W.,
- et al.,
- CHARISMA Investigators
- Yeh R.W.,
- Kereiakes D.J.,
- Steg P.G.,
- et al.,
- DAPT study investigators
- ↵AstraZeneca. Prescribing information for Brilinta. U.S. Food and Drug Administration. 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022433s017lbl.pdf. Accessed June 28, 2016.
- Udell J.A.,
- Bonaca M.P.,
- Collet J.P.,
- et al.
- Bonaca M.P.,
- Bhatt D.L.,
- Steg P.G.,
- et al.
- Tantry U.S.,
- Bonello L.,
- Aradi D.,
- et al.,
- Working group on On-Treatment Platelet Reactivity
- Roe M.T.,
- Goodman S.G.,
- Ohman E.M.,
- et al.
- Kereiakes D.J.,
- Yeh R.W.,
- Massaro J.M.,
- et al.,
- DAPT Study Investigators
- Magnani G.,
- Storey R.F.,
- Steg G.,
- et al.
- James S.,
- Budaj A.,
- Aylward P.,
- et al.
- Bonaca M.P.,
- Bhatt D.L.,
- Storey R.,
- et al.
- Fournier N.,
- Toesca R.,
- Bessereau J.,
- et al.