Today physicians managing patients with an acute coronary syndrome (ACS) have a choice among three oral products intended to reduce the risk of thrombotic events by decreasing platelet aggregation. These drugs are clopidogrel (Plavix, approved by the FDA in 1997), prasugrel (Effient, approved in 2009), and ticagrelor (Brilinta, approved in 2011). Prasugrel and ticagrelor are available only as branded products, but generic clopidogrel is on the market. At a retail price of about $0.40 per day, generic clopidogrel enjoys a substantial price advantage, as prasugrel and ticagrelor cost at least 20 times as much. Price alone would seem to make generic clopidogrel the obvious choice in managed care, but these P2Y12 inhibitors aren’t sufficiently similar to make the choice easy.
First, a substantial percentage of patients are poor responders to clopidogrel, often owing to gene polymorphisms, notably the following (Campo 2011):
- ABCB1*2,The Arabic numeral following the asterisk designates the specific polymorphism according to the order of first publication; the symbol for the gene precedes the asterisk. associated with increased expression of an intestinal glycoprotein that ushers environmental toxins and drugs out of cells, leading to decreased absorption of clopidogrel. Carriers are at increased risk of death, MI, and stroke when they receive clopidogrel.
- CYP2C19*2, which encodes a nonfunctional cytochrome P450 enzyme resulting in decreased conversion of clopidogrel, a prodrug, into its active metabolite. Found in about 25% of Caucasians, this polymorphism is associated with an increased risk of death, MI, and stent thrombosis when carriers receive clopidogrel at the usual dose.
- CYP2C19*17, a mutation associated with increased transcription of the gene, causing clopidogrel to be metabolized more rapidly.
Unfortunately, the clinical utility of genetic screening tests aimed at personalizing clopidogrel therapy [or prasugrel therapy, for that matter, in which the 2C19 alleles also may come into play (Cuisset 2012)] hasn’t been adequately demonstrated yet, no doubt because genetic factors affecting metabolism are only a portion of the many factors that influence a patient’s response to clopidogrel (Steinhubl 2010).
Second, in the clinical trials that led to their FDA approval, both prasugrel and ticagrelor were compared with clopidogrel, and each outperformed clopidogrel in many respects. Third, ticagrelor brings with it some adverse effects, notably dyspnea, that aren’t seen with clopidogrel or prasugrel and that could affect patients’ adherence to therapy In PLATO, the phase 3 trial of ticagrelor, discontinuation rates owing to dyspnea were 0.9% and 0.1% among patients receiving ticagrelor and clopidogrel, respectively..
Fourth, oral antiplatelets are used in conjunction with aspirin, and in the complicated setting of ACS they may be used concurrently with or instead of many other drugs, including intravenous glycoprotein IIb/IIIa inhibitors, intravenous or subcutaneous anticoagulants, oral anticoagulants, and proton pump inhibitors, further complicating the decision-making process.
In the absence of definitive head-to-head trials of prasugrel and ticagrelor, researchers have turned to pharmacodynamic analyses and meta-analyses in an attempt to determine whether or not one drug has an edge over another. Several such studies have been published recently and will be discussed below, along with some ongoing studies aimed at clarifying the role of oral antiplatelets.
During the decades-long evolution of oral antiplatelet medications for reducing the risk of thrombotic events in patients with ACS, the challenge has been to achieve an acceptable balance between preventing thrombosis and avoiding hemorrhage — navigating between Scylla and Charybdis, as one commenter put it (Bhatt 2007). After oral agents that block glycoprotein IIb/IIIa receptors were found to be counterproductive — they increased the risk of major bleeding but failed to reduce the risk of ischemic events — attention turned to the oral antiplatelets that work, at the molecular level, by inhibiting the P2Y12 adenosine diphosphate (ADP) platelet receptor. Blocking this receptor reduces platelet reactivity, thereby lowering the risk of thrombosis. One such drug, ticlopidine, was used together with aspirin to reduce the risk of stent thrombosis in patients receiving coronary stents, helping to make this intervention common. But when clopidogrel was found to have similar efficacy and a better safety profile than ticlopidine, ticlopidine fell by the wayside as the combination of clopidogrel and aspirin came to be used to treat patients with all forms of ACS. Clopidogrel has its flaws, as previously noted. That left room for prasugrel and ticagrelor to enter the fray.
Apparently reflecting the absence of a clearly superior product, the three largest commercial PBMs (Medco, Express Scripts National Preferred Formulary, and Caremark) all designate Brilinta, Effient, and generic clopidogrel as preferred products, excluding only branded Plavix. In addition, the most recent guidelines issued jointly by the American College of Cardiology and the American Heart Association for UA/NSTEMI (unstable angina and non-ST-segment-elevation myocardial infarction, Jneid 2012), STEMI (ST-segment-elevation myocardial infarction, Kushner 2009), and percutaneous coronary intervention (PCI) (Levine 2011) don’t make much of a distinction among clopidogrel, prasugrel, and ticagrelor, but that doesn’t mean the drugs are interchangeable in all cases.
Clopidogrel and prasugrel are prodrugs that require oxidation via cytochrome P-450 isoenzymes to become active metabolites. The active compounds bind irreversibly to the P2Y12 platelet receptor for the life of the platelet (7 to 10 days), preventing platelet activation and aggregation. This characteristic is of great concern whenever patients need bypass surgery immediately, but of less importance when surgery isn’t being considered or when it’s elective.
In contrast, ticagrelor needs no metabolic action to become active, and its metabolite also is active. In theory, this could enable ticagrelor to inhibit platelet activation more rapidly than prasugrel. A team of Greek cardiologists recently conducted a head-to-head pharmacodynamics study, in STEMI patients undergoing PCI, with the expectation that it would confirm this hypothesis. To the cardiologists’ surprise, they found no statistically significant difference in platelet reactivity at 1 hour (the primary endpoint) between patients randomized to ticagrelor vs. prasugrel or at 2, 6, or 24 hours (Alexopoulos 2012). By day 5, platelet reactivity was statistically significantly lower in the ticagrelor group than in the prasugrel group, but any clinical significance of this difference remains unknown.
In both arms of the study, however, rates of high on-treatment platelet reactivity (HTPR) were high initially, ranging from 45% to 67% in the prasugrel group and 52% to 74% in the ticagrelor group at hour 1, and from 32% to 46% in the ticagrelor group and 20% to 35% in the prasugrel group at hour 2; none of the between-group differences were statistically significant at any time point.
The authors say that in the setting of STEMI and PCI, where rapid and robust platelet inhibition is important, further improvement is necessary, perhaps in the form of higher loading doses of P2Y12 inhibitors, administration of P2Y12 inhibitors before hospitalization, or concurrent use of a fast-acting intravenous platelet inhibitor to address the initial lack of antiplatelet action seen with both drugs.
Other researchers have tried to use meta-analysis to delineate clinical differences among clopidogrel, prasugrel, and ticagrelor in ACS. One recent meta-analysis (Aradi 2012) included four randomized controlled trials (RCTs) in which clopidogrel was compared with placebo (n=64,027) and five RCTs in which prasugrel or ticagrelor was compared with clopidogrel (n=43,446), including a prasugrel study published in late 2012 (Roe 2012). The researchers excluded RCTs enrolling fewer than 500 subjects to reduce the effect of small-study bias on their primary endpoint, the risk of stroke. In the placebo-controlled RCTs, clopidogrel was associated with modest statistically significant reductions in the rates of MI, total stroke, and a composite endpoint (CV death, MI, and stroke) and a slight but still statistically significant reduction in the rate of CV death (Table 1). However, there was no statistically significant difference between rates of hemorrhagic stroke in the clopidogrel and placebo groups. When clopidogrel served as the active comparator in the RCTs of prasugrel or ticagrelor, prasugrel or ticagrelor was associated with statistically significant reductions in rates of MI, CV death, and the composite endpoint but not in rates of total stroke or hemorrhagic stroke.
|Table 1 Meta-analysis of RCTs pitting clopidogrel vs. placebo, and prasugrel and ticagrelor vs. clopidogrel |
|Clopidogrel vs Placebo |
|Endpoint ||Clopidogrel |
|ARD, clopidogrel vs placebo ||Odds ratio |
|P value |
|Myocardial infarction ||945 / 32,025 (2.95%) ||1165 / 31,996 (3.64%) ||–0.69% ||0.80 (0.74–0.88) ||<.001 |
|CV death ||2039 / 32,025 (6.37%) ||2181 / 31,996 (6.82%) ||–0.45% ||0.93 (0.87–0.99) ||.02 |
|Total stroke ||317 / 32,025 (0.99%) ||379 / 31,996 (1.18%) ||–0.19% ||0.84 (0.72–0.97) ||.02 |
|Hemorrhagic stroke ||70 / 30,953 (0.23%) ||73 / 30,913 (0.24%) ||–0.01% ||0.96 (0.69–1.33) ||.79 |
|Composite: CV death, MI, stroke ||9.21% ||10.44% ||–1.24% ||0.84 (0.76–0.93) ||<.001 |
|Prasugrel / ticagrelor vs clopidogrel |
|Endpoint ||Clopidogrel |
|Prasugrel / ticagrelor |
|ARD, prasugrel or ticagrelor vs clopidogrel ||Odds ratio |
|P value |
|Myocardial infarction ||1624 / 21,330 (7.61%) ||1397 / 22,122 (6.32%) ||–1.29% ||0.83 (0.74–0.93) ||<.001 |
|CV death ||926 / 21,330 (4.34%) ||809 / 22,122 (3.66%) ||–0.68% ||0.86 (0.78–0.94) ||.002 |
|Total stroke ||236 / 21,330 (1.11%) ||253 / 22,122 (1.14%) ||+0.03% ||1.06 (0.88–1.26) ||.55 |
|Hemorrhagic stroke ||50 / 20,878 (0.24%) ||60 / 21,347 (0.28%) ||+0.04% ||1.16 (0.75–1.81) ||.49 |
|Composite: CV death, MI, stroke ||11.65% ||9.97% ||–1.68% ||0.85 (0.79–0.92) ||<.001 |
|ARD=absolute risk difference, CI= confidence interval; CV=cardiovascular, MI=myocardial infarction |
Source: Aradi 2012
A head-to-head contest, sort of
In an effort to identify clinical differences between prasugrel and ticagrelor in lieu of head-to-head studies, a group of Italian researchers conducted an indirect meta-analysis in patients with ACS, using two RCTs in which ticagrelor was compared with clopidogrel (PLATO and DISPERSE-2) and TRITON TIMI 38, which compared prasugrel with clopidogrel (Biondi-Zoccai 2010). (For a discussion of the validity of this approach, see Song 2003.) These RCTs were among the five studies of prasugrel/ticagrelor vs. clopidogrel used in the meta-analysis mentioned above; of the two studies that weren’t used, one enrolled patients undergoing urgent or elective PCI (Wiviott 2005), some of whom (the elective patients) didn’t have ACS and thus had a much lower risk of stent thrombosis, and the other (Roe 2012) hadn’t been published.
In the meta-analysis by Biondi-Zoccai et al, the pooled data for prasugrel and ticagrelor show that, compared with clopidogrel, these drugs reduced the risk of the composite endpoint and overall death by 17%, nonfatal MI by 21%, and stent thrombosis by 39% (Table 2). Clopidogrel performed statistically significantly better than prasugrel and ticagrelor, however, with respect to major bleeding unrelated to bypass, major or minor bleeding, and drug discontinuation.
|Table 2 Indirect meta-analysis of RCTs comparing prasugrel and ticagrelor with clopidogrel |
|Ticagrelor and prasugrel vs clopidogrel — efficacy analysis |
|Endpoint ||Prasugrel / ticagrelor |
(events / patients [rate])
(events / patients [rate])
|ARD, prasugrel & ticagrelor vs clopidogrel ||Odds ratio* |
|P value |
|Composite: overall death, nonfatal MI, nonfatal stroke ||1613 / 16,480 (9.79%) ||1904 / 16,413 (11.60%) ||–1.81% ||0.83 (0.77–0.89) ||<.001 |
|Overall death ||594 / 16,480 (3.60%) ||707 / 16,413 (4.31%) ||–0.70% ||0.83 (0.74–0.93) ||.001 |
|Nonfatal MI ||991 / 16,480 (6.01%) ||1228 / 16,413 (7.48%) ||–1.47% ||0.79 (0.73–0.86) ||<.001 |
|Nonfatal stroke ||198 / 16,480 (1.20%) ||167 / 16,413 (1.02%) ||+0.18% ||1.12 (0.91–1.38) ||.28 |
|Stent thrombosis, definite or probable ||188 / 12,062 (1.56%) ||300 / 12,071 (2.49%) ||–0.93% ||0.61 (0.51–0.74) ||<.001 |
|Ticagrelor and prasugrel vs clopidogrel — safety analysis |
|Major bleeding ||953 / 16,310 (5.23%) ||781 / 16,229 (4.81%) ||+0.42% ||1.09 (0.99–1.21) ||.08 |
|Major bleeding unrelated to bypass ||367 / 15,976 (2.30%) ||288 /15,902 (1.81%) ||+0.49% ||1.27 (1.09–1.49) ||.002 |
|Major bleeding related to bypass ||470 / 15,976 (2.94%) ||482 / 15,902 (3.03) ||–0.09% ||0.97 (0.85–1.10) ||.63 |
|Bleeding, major or minor ||1249 / 15,976 (7.82%) ||1137 / 15,902 (7.15%) ||+0.67% ||1.10 (1.01–1.20) ||.02 |
|Minor bleeding ||431 / 16,310 (2.64%) ||386 / 16,229 (2.38%) ||+0.26% ||1.11 (0.97–1.28) ||.13 |
|Drug discontinuation ||2695 / 16,480 (16.35%) ||2453 / 16,413 (14.95%) ||+1.41% ||1.12 (1.05–1.19) ||<.001 |
|*Odds ratio <1.0 favors prasugrel and ticagrelor; odds ratio >1.0 favors clopidogrel |
ARD=absolute risk difference, CI= confidence interval; MI= myocardial infarction
Source: Biondi-Zoccai 2010
In the head-to-head comparison of prasugrel and ticagrelor, there were no statistically significant differences in the composite endpoint, overall death, nonfatal MI, and nonfatal stroke (Table 3). The risk of stent thrombosis, however, was 36% lower with prasugrel, but prasugrel also was associated with a statistically significant increase in the risk of major bleeding, major bleeding associated with bypass surgery, and major or minor bleeding.
|Table 3 Prasugrel vs. ticagrelor |
|Endpoint ||Odds ratio* (95% CI) ||P value |
|Composite: death, MI, or stroke ||0.99 (0.86–1.33) ||.86 |
|Death ||1.22 (0.96–1.55) ||.11 |
|MI ||0.89 (0.75–1.06) ||.20 |
|Stroke ||0.86 (0.55–1.33) ||.49 |
|Stent thrombosis, definite or probable ||0.64 (0.43–0.93) ||.02 |
|Major bleeding ||1.43 (1.10–1.86) ||.007 |
|Major bleeding not related to bypass ||1.06 (0.77–1.45) ||.74 |
|Major bleeding related to bypass ||4.30 (1.74–10.64) ||.002 |
|Major or minor bleeding ||1.27 (1.04–1.55) ||.02 |
|Minor bleeding ||1.07 (0.79–1.45) ||.65 |
|Drug discontinuation ||1.03 (0.88–1.20) ||.73 |
|*Odds ratio <1.0 favors prasugrel; odds ratio >1.0 favors ticagrelor |
CI= confidence interval, MI= myocardial infarction
Source: Biondi-Zoccai 2010
The authors believe their study could help guide treatment decisions for individual patients, as follows:
- Either prasugrel or ticagrelor could be considered instead of clopidogrel in ACS patients who aren’t at high risk of bleeding.
- Because prasugrel appears to be more effective than ticagrelor in preventing stent thrombosis, in ACS patients who are undergoing PCI with drug-eluting stents and who aren’t at high risk of bleeding, prasugrel could be started at the time of PCI.
- Ticagrelor could be best for ACS patients without severe bleeding risk who are to be managed by an initial conservative strategy.
- Ticagrelor may be a better choice than prasugrel if urgent CABG is likely.
- Clopidogrel may remain the best choice for patients with high risk of bleeding (e.g., history of stroke, advanced age, severe renal impairment).
- Owing to its low cost, clopidogrel may be more attractive than prasugrel or ticagrelor in patients with low risk of ischemia or high risk of bleeding.
As appealing as genetic assays are, a genetic profile of a patient usually is insufficient in itself to guide treatment decisions. That’s because interactions among genes are complex, and because genes interact with many factors in the environment in which the genes exist (“environment” meaning the person’s body and the world in which that body lives). Given these circumstances, some experts think that combining genotypic information with phenotypic information will provide a practical way to match patients with antiplatelet medications. For example, genetic screening showing an absence of loss-of-function genes such as CYP2C19*2 might suggest that a patient is likely to achieve acceptable platelet reactivity values if clopidogrel is used, but if the patient has diabetes, which is associated with high platelet reactivity values when the treatment is clopidogrel, prasugrel or ticagrelor might be a better choice (Campo 2011).
To test the idea of using genotypic and phenotypic information to help clinicians select the most appropriate antiplatelet medication for a given patient, the Italian Society of Invasive Cardiology launched a 4,000-patient study, GENE-MATRIX (NCT01477775), in January 2012. The investigators are comparing standard practice (i.e., physician’s exercise of clinical judgment to choose clopidogrel, prasugrel, or ticagrelor) with an algorithm incorporating phenotypic and genotypic information to determine drug choice for patients who underwent coronary angioplasty with stent emplacement.
Their hope is that the algorithm will increase the percentage of patients who achieve the therapeutic range for P2Y12 activity after 30 days to 70% (compared with 50% of patients receiving standard care), and that this improvement will translate into improved outcomes after one year.
This study is expected to be completed by December 2015, with all data for the primary outcome (time to first occurrence of cardiovascular death, MI, stroke, or type, 2, 3, or 5 bleeding as defined by the Bleeding Academic Research Consortium) in hand by December 2014.
Meanwhile, the Agency for Healthcare Research and Quality (AHRQ) is underwriting a comparative effectiveness review of the medical literature in an attempt to answer important unresolved questions (Table 4) surrounding the use of P2Y12 blockers and related drugs in the setting of UA/NSTEMI (AHRQ 2012). But when the final report is posted on the AHRQ web site, many of these questions are likely to remain unresolved, owing to the lack of head-to-head studies of the new oral antiplatelet agents. In the draft being circulated for peer review prior to posting of the final report, 17 outcomes of interest are listed involving comparisons among clopidogrel, ticagrelor, and prasugrel.
|Table 4 Key questions surrounding the use of oral antiplatelets and related drugs in UA/NSTEMI |
|Key questions ||Interventions ||Comparators |
1. In patients undergoing an early invasive approach (before cardiac catheterization or during PCI) for treating UA/NSTEMI:
- What are the comparative effectiveness (dose and timing) and comparative safety of an intravenous glycoprotein IIb/IIIa inhibitor versus oral antiplatelet agent as initial therapy before going to the catheterization laboratory?
- What are the comparative effectiveness (dose and timing) and comparative safety of coadministration of intravenous or oral antiplatelet agents in patients undergoing PCI for improving cardiovascular outcomes? Do the effectiveness and safety vary based on which initial anticoagulant is used or the combination of anticoagulant and antiplatelet agents?
- Based on demographic and other clinical characteristics, are there subgroups of patients for whom the effectiveness and safety differ?
IV glycoprotein IIb/IIIa inhibitors
- Unfractionated heparin
- Before catheterization — dose and timing of intravenous or oral antiplatelets with anticoagulants plus aspirin
- During PCI — dosing and timing of IV or oral antiplatelet with anticoagulants, plus aspirin
2. In patients undergoing an initial conservative approach for treating UA/NSTEMI:
- What are the comparative effectiveness (dose and timing) and comparative safety of different anticoagulants on improving cardiovascular outcomes?
- What are the comparative effectiveness (dose and timing) and comparative safety of different antiplatelet agents on improving cardiovascular outcomes?
- Based on demographic and other characteristics, are there subgroups of patients for whom the effectiveness and safety differ?
- Unfractionated heparin
- Dosing and timing of anticoagulant plus aspirin
- Dosing and timing of oral antiplatelets plus aspirin
3. In patients treated for UA/NSTEMI post discharge:
- What are the comparative effectiveness (dose and duration) and comparative safety of the oral antiplatelet agents given in combination with aspirin? Do the effectiveness and safety vary based on the dose of aspirin used?
- What are the comparative effectiveness and comparative safety of PPIs for reducing bleeding events in patients receiving dual antiplatelet therapy after UA/NSTEMI? Do the effectiveness and safety vary by oral antiplatelet therapy and PPI?
- In patients with an indication for long-term anticoagulant therapy, what are the comparative effectiveness and comparative safety of adding an oral anticoagulant to aspirin and another antiplatelet agent for improving cardiovascular outcomes?
- Based on demographic and other characteristics, are there subgroups of patients for whom the effectiveness and safety differ?
Proton pump inhibitors
- Dose and duration of oral antiplatelets in combination with aspirin at different doses
- PPIs vs no PPIs
- Dual antiplatelet therapy (aspirin with oral antiplatelet) vs triple therapy (oral anticoagulant, aspirin, and oral antiplatelet)
|Source: AHRQ 2012 |
For eight outcomes, including all-cause mortality at 30 days and cardiovascular mortality at 30 days, the strength of the evidence is rated as insufficient, and for seven others the strength of evidence is rated as low. For only two composite outcomes (CV mortality, nonfatal MI, or nonfatal stroke at 30 days and one year) is the strength of evidence deemed moderate.
In sum, the question of which oral antiplatelet is best for a given patient remains clouded by clinical uncertainty, and the sun isn’t going to break through any time soon. As the indirect meta-analysis by Aradi et al suggests, it seems likely that each P2Y12 blocker has an important role to play in the diverse ACS population, but much of the evidence for more clearly defining those roles has yet to emerge.
Agency for Healthcare Research and Quality (AHRQ). Antiplatelet and Anticoagulant Treatments for Unstable Angina/Non-ST Elevation Myocardial Infarction. Draft research review. November 1, 2012. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/374/1309/UA-NSTEMI_DraftReport_20121101.pdf
Agency for Healthcare Research and Quality (AHRQ). Antiplatelet and Anticoagulant Treatments for Unstable Angina/Non-ST Elevation Myocardial Infarction. December 13, 2012. Available at: http://effectivehealthcare.ahrq.gov/ehc/products/374/954/UA-NSTEMI_AmendedProtocol_20121213.pdf
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