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Abstract
Background: Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study.
Methods: In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non–ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor.
Results: ADP- and non–ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32–72] versus 83 [63–103]; least-square means difference: –31; 95% confidence interval, –57 to –4; P=0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points.
Conclusions: In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non–ADP-induced platelet reactivity was not significantly different between the 2 agents.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01852214.
Introduction
Editorial, see p 793
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, and DM patients who experienced an ischemic event have greater morbidity and mortality than non-DM patients.1,2 Although the mechanism leading to the greater atherothrombotic risk in DM patients is multifactorial, increased platelet reactivity plays a key role underscoring the importance of antiplatelet treatment.3,4 Clopidogrel is still the most widely used P2Y12 receptor antagonist that, in adjunct to aspirin, reduces ischemic event rates in patients with coronary artery disease (CAD).5 However, pharmacodynamic (PD) studies have consistently shown reduced clopidogrel-induced antiplatelet effects among DM compared with non-DM patients, which have been mainly attributed to impaired pharmacokinetics characterized by lower active metabolite levels.6,7 These observations may, at least in part, account for the increased risk of ischemic recurrences, including stent thrombosis, among DM patients, underscoring the need for more effective platelet inhibiting therapies.3,4
Prasugrel and ticagrelor are the 2 latest-generation P2Y12 receptor antagonists with important pharmacological advantages compared with clopidogrel. In particular, they are associated with enhanced platelet inhibition and greater reduction in atherothrombotic recurrences, albeit at the expense of increased bleeding, in patients with acute coronary syndrome.5 Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be heightened with prasugrel.8–11 Because the ischemic benefits of prasugrel and ticagrelor are mainly attributed to their enhanced platelet inhibitory effects,12,13 it has been suggested that these observations may be attributable to the PD differences between these 2 agents in DM patients. However, the comparative PD effectiveness of prasugrel and ticagrelor in the loading and maintenance phases of treatment in patients with DM remains poorly explored and represented the aim of this investigation.
Methods
Study Design and Patient Population
The OPTIMUS-4 study (Optimizing Antiplatelet Therapy in Diabetes Mellitus-4) was a prospective, randomized, double-blind, double-dummy, crossover study aimed to compare the PD effects of both loading dose (LD) and maintenance dose (MD) regimens of prasugrel versus ticagrelor among DM patients with CAD on a background of aspirin therapy (NCT01852214). Patients were screened at the outpatient cardiology clinics of University of Florida Health-Jacksonville and were considered eligible for the study if they met all of the following inclusion criteria: (1) age between 18 and 74 years; (2) type 2 DM on treatment with oral hypoglycemic agents or insulin; (3) angiographically documented CAD (>50% stenosis in a major epicardial coronary vessel); and (4) on maintenance treatment with low-dose aspirin (81 mg once daily) for at least 30 days as per standard of care. DM status was defined according to American Diabetes Association criteria.14 Patients were excluded if any of the following criteria were present: (1) history of stroke, transient ischemic attack, or intracranial bleeding; (2) known allergies to prasugrel or ticagrelor; (3) weight <60 kg; (4) on treatment with a P2Y12 receptor antagonist or an oral anticoagulant in the previous 30 days; (5) clinical indication to be on treatment with a P2Y12 receptor antagonist (ie, acute coronary syndrome or coronary stenting procedure in the past 12 months); (6) hemoglobin A1c ≥ 10% within 3 months; (7) blood dyscrasia or bleeding diathesis; (8) active bleeding; (9) platelet count <80×103/mL; (10) hemoglobin <10g/dL; (11) hemodynamic instability; (12) creatinine clearance <30 mL/min; (13) hepatic dysfunction (baseline alanine aminotransferase >2.5 times the upper limit of normal); (14) sick sinus syndrome or high-degree atrioventricular block without a pacemaker; (15) treatment with drugs interfering with cytochrome P450 3A4 metabolism; and (16) pregnant or lactating females. The study complied with the Declaration of Helsinki, was approved by University of Florida Institutional Review Board, and all patients gave their written informed consent.
With the use of a computer-based randomization system, patients were assigned randomly (1:1) to receive either prasugrel or ticagrelor. Patients randomly assigned to prasugrel were treated with a 60 mg LD followed by 10 mg once daily MD (plus placebo-ticagrelor tablets twice daily); the MD of prasugrel (or placebo-prasugrel) was initiated 24 hours after the LD. Patients randomly assigned to ticagrelor were treated with a 180 mg LD followed by 90 mg twice daily MD (plus placebo-prasugrel tablets once daily); the MD of ticagrelor (or placebo-ticagrelor) was started 12 hours after the LD. Randomized treatment was maintained for 1 week (7±2 days). After completion of the 1-week treatment period, patients discontinued the study medications for 2 to 4 weeks (wash-out period) and then crossed over to the alternate treatment, which was administered for 1 week. Aspirin 81 mg once daily was maintained throughout the study.
Investigators, laboratory personnel, and patients were blinded to treatment assignments. Prasugrel, ticagrelor, and placebo tablets were encapsulated and distributed by our institutional pharmacy to guarantee the blind. In particular, patients randomly assigned to prasugrel received a LD with six 10-mg prasugrel tablets plus 2 placebo-ticagrelor tablets followed by MD with prasugrel 10 mg once daily plus placebo-ticagrelor twice daily. Patients randomly assigned to ticagrelor received a LD with two 90-mg ticagrelor tablets plus 6 placebo-prasugrel tablets followed by MD with ticagrelor 90 mg twice daily plus placebo-prasugrel once daily. Compliance to treatment was assessed by pill count and patient interview. Blood sampling for PD testing was performed at a total of 8 time points using 4 different assays as described below. A flow diagram of the study is represented in Figure 1.
Study design. CAD indicates coronary artery disease; DM, diabetes mellitus; LD, loading dose; and MD, maintenance dose.
Blood Sampling and PD Testing
Blood sampling for PD testing was performed at 4 time points for each study sequence (total of 8 time points): baseline (before randomization), 30 minutes, and 2 hours after LD (to assess the acute PD effects associated with the LD), and after 1 week (7±2 days) of randomized MD treatment (to assess the chronic PD effects associated with the MD). To ensure measurement of trough levels of platelet reactivity, the 1-week blood sample was collected 12 hours after the last MD of ticagrelor or placebo-ticagrelor, and 24 hours after the last dose of prasugrel or placebo-prasugrel and aspirin.
PD testing was performed using 4 different assays: (1) VerifyNow P2Y12 point-of-care testing (VN-P2Y12); (2) whole blood vasodilator-stimulated phosphoprotein (VASP); (3) light transmittance aggregometry (LTA); (4) multiple electrode aggregometry (MEA). In brief, the VN-P2Y12 assay (Accriva) measures platelet-induced aggregation as an increase in light transmittance and reports results in P2Y12 reaction units (PRUs).15 VASP was measured by quantitative flow cytometry using commercially available labeled monoclonal antibodies according to standard protocols (Biocytex Inc) and quantified by the platelet reactivity index (PRI).15 LTA was conducted using platelet-rich plasma by the turbidimetric method in a 2-channel aggregometer (Chrono-Log 490 Model, Chrono-Log Corp) after 5 and 20 μmol/L ADP stimuli; curves were recorded for 6 minutes, and maximal platelet aggregation (MPA) was determined as percent change in light transmittance.15 MEA was assessed in whole blood by the Multiplate analyzer (Dynabyte Medical), as described previously.16 This instrument can perform up to 5 parallel aggregometry measurements assessing the change in impedance caused by the adhesion of platelets onto sensor units formed by silver-covered electrodes. Agonists were selected to explore ADP- and non–ADP (thromboxane A2-, collagen-, and thrombin-mediated)-induced pathways of platelet aggregation. These included ADP 6.4 μmol/L, with and without prostaglandin E1 9.4 nmol/L, arachidonic acid 0.5 mmol/L, collagen 3.2 μg/mL, and thrombin receptor–activating peptide 32 μmol/L. The mean values of 2 independent determinations are expressed as the area under the curve of the aggregation tracing and quantified by an area under the curve of arbitrary units (AUs × minute).16
In line with expert consensus, high on-treatment platelet reactivity (HPR) was defined as follows: PRU >208 (VN-P2Y12), PRI >50% (VASP), MPA >59% (LTA 20 μmol/L ADP), MPA >46% (LTA 5 μmol/L ADP), or area under the curve >460 (MEA – ADP).17 Because LTA results with 5 μmol/L ADP were consistent with 20 μmol/L ADP, these are reported in the online-only Data Supplement Figure I.
Sample Size Calculation and Study End Points
The primary end point of the study was the comparison of PRU determined by VN-P2Y12 at 1 week between prasugrel and ticagrelor. Because there were no preliminary data available at the time of study design, we chose an arbitrary sample of 50 patients.18 Assuming a common standard deviation of 20 PRU and a ≈10% rate of invalid results because of hemolysis or drop-out, this sample would allow us to detect an absolute reduction of 10 PRU with prasugrel in comparison with ticagrelor after 1 week of randomized treatment with a 90% power and 2-sided α=0.05. This approach is in line with the recommendation for pilot investigations.18 A 10 PRU absolute difference was chosen as a reference value because, in a large meta-analysis, a 4% increase in cardiac events occurred for every 10-U increase in PRU.19 Additional assessments included PD comparisons at all time points using all assays, and comparisons of HPR rates. Adverse events, including ischemic and bleeding events, during the study period were recorded. Bleeding events were classified according to the Bleeding Academic Research Consortium definition.20
Statistical Analysis
For baseline characteristics, continuous variables are expressed as mean±standard deviation, and categorical variables are expressed as frequencies and percentages. Conformity to the normal distribution was evaluated for continuous variables with the Kolmogorov-Smirnov test. Treatment effects were evaluated comparing the functional parameters observed in the overall patient population after prasugrel treatment with those achieved after ticagrelor regardless of the sequence. All statistical comparisons of platelet function for the primary end point and secondary end points with continuous variables were conducted using a linear mixed-effect model with treatment group, sequence, period, and treatment-group-by-period as fixed effects, patient as a random effect, and baseline value of the corresponding platelet function test as a covariate. Exploratory analyses were conducted to compare platelet reactivity levels between prasugrel and ticagrelor in each period, measured as PRU and PRI, using an analysis of variance method with a general linear model. The comparisons of rates of HPR were conducted using the McNemar test. A 2-tailed P value of <0.05 was considered to indicate a statistically significant difference for all the analyses performed. Platelet reactivity results are reported as least-square means (LSM) (95% confidence interval [CI]) for the above detailed analyses. Statistical analysis was performed using SPSS version 22.0 software (SPSS Inc.).
All analyses of platelet function and HPR were conducted on the PD population, which was defined as all randomly assigned subjects who received study drug, successfully completed at least 1 treatment period of the study, and had valid data for the primary end point (PRU at 1 week). Safety analyses were conducted on the safety population, which included all patients exposed to at least 1 dose of the study drug. The corresponding author had full access to all the data in the study and assumes responsibility for the accuracy and completeness of the data and all the analyses, and for the fidelity of this report to the trial protocol, as well.
Results
Patient Population
Between February 2013 and July 2015, a total of 61 DM patients with CAD on aspirin treatment agreed to participate in the study; 11 patients were excluded, and thus a total of 50 patients were assigned randomly (prasugrel, n=26; ticagrelor, n=24). The randomized cohort was exposed to at least 1 dose of study medication and represented the safety population. Overall, 4 patients withdrew from the study before the completion of the first treatment period: 1 initially randomly assigned to prasugrel (dyspnea, n=1) and 3 initially randomly assigned to ticagrelor (dyspnea, n=2; withdrawal of consent, n=1). Thus, a total of 46 patients met criteria to be included in the PD population. Demographic and baseline characteristics of the PD population are summarized in the Table. No ischemic or the Bleeding Academic Research Consortium type 2 to 5 bleeding events were observed in the safety population during the overall study time course. Two patients (prasugrel, n=1; ticagrelor, n=1) had Bleeding Academic Research Consortium type 1 bleeding. Dyspnea was reported in 9 (18%) patients treated with ticagrelor and in 3 (6%) treated with prasugrel. Dyspnea led to study drug discontinuation in 3 patients treated with ticagrelor and 1 patient treated with prasugrel. Patient disposition is summarized in Figure 2.
Baseline Characteristics of the PD Population
Trial profile. HBA1c, hemoglobin A1c; and PD, pharmacodynamic.
Pharmacodynamic Findings
ADP-Induced Platelet Reactivity
At baseline, while on aspirin therapy, platelet reactivity was not significantly different between groups with all 4 assays. After administration of the LD, ADP-induced platelet reactivity decreased over time in both groups and with all assays (P<0.001 for all assays). In comparison with baseline, intragroup comparisons showed that the reduction in platelet reactivity for both prasugrel and ticagrelor was evident as early as at 30 minutes, reaching statistical significance for some but not all assays (VN-P2Y12 [prasugrel, P=0.393; ticagrelor, P=0.055]; VASP [prasugrel, P=0.006; ticagrelor, P=0.064]; LTA [prasugrel, P=0.001; ticagrelor, P=0.041]; MEA ADP [prasugrel, P=0.002; ticagrelor, P=0.010]), and was sustained at 2 hours (P<0.001 for all assays) up to 1-week (P<0.001 for all assays). In the intergroup comparisons platelet reactivity measured by VN-P2Y12 (Figure 3A) was not significantly different between prasugrel and ticagrelor at 30 minutes (P=0.222) and was numerically lower in ticagrelor-treated patients at 2 hours post-LD (LSM difference, –22; 95% CI, –48 to 3; P=0.086). The primary end point of PRU defined by VN-P2Y12 after 1 week of MD treatment showed significantly lower levels with ticagrelor in comparison with prasugrel (52 [32–72] versus 83 [63–103]; LSM difference, –31; 95% CI, –57 to –4; P=0.022). There was no treatment-group-by-period interaction (P=0.944). PRI measured by VASP was not significantly different between prasugrel and ticagrelor at all time points, including 1 week (Figure 3B). MPA measured by LTA with 20 μmol/L ADP (Figure 4A) and platelet aggregation measured by MEA with ADP stimuli (Figure 4B) and with ADP plus prostaglandin E1 (Figure II in the online-only Data Supplement) showed results similar to those defined by VASP.
Platelet reactivity measured by VerifyNow P2Y12 and VASP. Comparisons of P2Y12 reaction units (PRU) (A) and platelet reactivity index (PRI %) (B) across time points between prasugrel and ticagrelor. The dashed lines indicate thresholds for HPR. Data are presented as individual values. Solid lines with error bars indicate least-square means (95% confidence interval). HPR indicates high on-treatment platelet reactivity; and VASP, vasodilator-stimulated phosphoprotein.
Platelet reactivity measured by light transmittance aggregometry and multiple electrode aggregometry. Comparisons of maximal platelet aggregation (MPA %) (A) and area under the curve (AUC) (B) of the aggregation tracing across time points between prasugrel and ticagrelor after ADP stimuli. The dashed lines indicate thresholds for HPR. Data are presented as individual values. Solid lines with error bars indicate least-square means (95% confidence interval). HPR indicates high on-treatment platelet reactivity; LTA, light transmittance aggregometry; and MEA, multiple electrode aggregometry.
An exploratory analysis comparing PRU levels between prasugrel and ticagrelor in each period showed no significant differences in PRU values between prasugrel and ticagrelor at each time point of each period, with the exception of 1-week PRU in period 2 that was significantly lower in patients receiving ticagrelor (LSM difference, –47; 95% CI, –83 to –12; P=0.010; Figure 5A). The exploratory analysis comparing PRI levels between prasugrel and ticagrelor in each period showed no significant differences in platelet reactivity at each time point of each period (Figure 5B).
Platelet reactivity measured by VerifyNow P2Y12 and VASP in period 1 and period 2. Comparisons of P2Y12 reaction units (PRU) (A) and platelet reactivity index (PRI %) (B) across time points between prasugrel and ticagrelor. Data are presented as least-square means. VASP indicates vasodilator-stimulated phosphoprotein.
Rates of HPR markedly reduced over time with both prasugrel and ticagrelor, with no significant differences between the 2 agents at each time point and with all assays (Figure 6A through 6D). After 1 week of MD treatment, HPR assessed by VN-P2Y12 was present in only 1 patient receiving prasugrel (2%) and 2 patients receiving ticagrelor (5%). Similar rates were shown with LTA with 20 μmol/L ADP (prasugrel, 0%; ticagrelor, 7%). HPR rates at 1 week were higher when assessed by VASP (prasugrel, 20%; ticagrelor, 19%) and MEA (prasugrel, 18%; ticagrelor, 19%).
Rates of high on-treatment platelet reactivity across time points after prasugrel and ticagrelor administration. High on-treatment platelet reactivity was defined as P2Y12 reaction units (PRU) >208 (A), platelet reactivity index (PRI) >50% (B), maximal platelet aggregation (MPA) >59% (C), and area under the curve (AUC) >460 (D). Histograms represent rates. There are no significant differences between prasugrel and ticagrelor (P>0.10 for all comparisons).
Non–ADP-Induced Platelet Reactivity
Platelet aggregation induced by arachidonic acid reduced over time after prasugrel and ticagrelor administration. Compared with baseline (on aspirin monotherapy) arachidonic acid–induced aggregation was numerically reduced at 30 minutes and significantly reduced at 2 hours post-LD with both prasugrel and ticagrelor (P<0.001 for both), which was sustained after 1 week of MD treatment (prasugrel, P=0.023; ticagrelor, P=0.047). Thrombin receptor-activating peptide–induced aggregation was similar at 30 minutes but was significantly reduced at 2 hours after an LD of prasugrel or ticagrelor (P<0.001 for both) in comparison with baseline, and the effect was maintained at 1 week (P<0.001 for prasugrel, P=0.002 for ticagrelor). Collagen-induced platelet aggregation was numerically reduced at 30 minutes and significantly reduced at 2 hours after an LD of both prasugrel (P=0.010) and ticagrelor (P<0.001). After 1 week of MD treatment, this effect was sustained, although the difference in comparison with baseline was still significant with ticagrelor (P=0.034) but not with prasugrel (P=0.220). There was no difference between prasugrel and ticagrelor at each time point with all agonists (Figure 7A through 7C).
Non–ADP-induced platelet reactivity. Comparisons of platelet reactivity across time points between prasugrel and ticagrelor measured by multiple electrode aggregometry (MEA) after stimuli with arachidonic acid (AA)(A), thrombin receptor–activating peptide (TRAP)(B), and collagen (COLL)(C). Data are presented as individual values. Solid lines with error bars indicate least-square means (95% confidence interval).
Discussion
The present study is the first prospective, randomized, double-blind, double-dummy, crossover PD investigation comparing prasugrel versus ticagrelor during both the acute and maintenance phases of treatment, specifically conducted in patients with DM. The following findings were observed: (1) prasugrel or ticagrelor promptly (within 2 hours) achieved potent platelet inhibitory effects without significant PD differences between the prasugrel 60 mg and ticagrelor 180 mg LD regimens; (2) potent platelet inhibitory effects persisted after 1 week with both 10 mg once daily prasugrel and 90 mg twice daily ticagrelor MD during the maintenance phase of treatment, with ticagrelor achieving significantly lower levels of platelet reactivity when measured by PRU levels using VN-P2Y12 (primary end point); (3) there were no significant differences in platelet inhibitory effect of 10 mg once daily prasugrel and 90 mg twice daily ticagrelor MD during the maintenance phase of treatment as measured by VASP, LTA, and MEA; (4) HPR rates with prasugrel and ticagrelor were similar and markedly low as early as 2 hours after the LD and up to 1 week of MD treatment; (5) prasugrel and ticagrelor are associated with inhibitory effects on measures of non–ADP-induced, including thromboxane-, collagen-, and thrombin-, platelet reactivity.
DM is a pandemic currently affecting >150 million people worldwide and estimates suggest that this population will double during the next 20 years.21 Atherosclerotic macrovascular disease, including CAD, stroke, and peripheral artery disease, accounts for the majority of morbidity and mortality associated with DM.22 Moreover, DM is a key determinant of recurrent cardiovascular events in patients with acute coronary syndrome or those undergoing percutaneous coronary intervention.2–4 Multiple factors, such as hyperglycemia, oxidative stress, endothelial dysfunction, platelet dysfunction, and abnormal coagulation factors, contribute to the prothrombotic milieu that characterizes DM.3,4 Importantly, increased platelet reactivity may account for inadequate response (ie, reduced platelet inhibitory effects) to oral antiplatelet agents, including the P2Y12 receptor antagonist clopidogrel, used for the prevention of ischemic events.3,4 Studies have consistently shown reduced antiplatelet effect of clopidogrel among DM patients in comparison with non-DM patients,3,4,6,7,23,24 which is mainly attributable to impaired pharmacokinetics, characterized by lower active metabolite levels, and only modestly attributed to an upregulation of the P2Y12 pathway.6 Prasugrel and ticagrelor have more favorable pharmacological profiles than clopidogrel, which translates into more prompt, potent, and predictable platelet inhibition.5 Subgroup analysis of patients with DM in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38) showed a reduction in ischemic events of prasugrel in comparison with clopidogrel (12.2% versus 17.0%; hazard ratio, 0.70; 95% CI, 0.58–0.85; P<0.001), which was consistent with the overall trial findings (P interaction=0.09), with no differences in major bleeding.8 Subgroup analysis of patients with DM in the PLATO trial (Study of Platelet Inhibition and Patient Outcomes) also showed that, in comparison with clopidogrel, ticagrelor reduced ischemic events (14.1% versus 16.2%; hazard ratio, 0.88; 95% CI, 0.76–1.03) consistently with the overall trial results (P interaction=0.49), without differences in major bleeding.9 However, although the absolute risk reduction in ischemic events with ticagrelor was higher in DM patients than in non-DM patients (DM, 2.1%; non-DM, 1.8%), the magnitude of such ischemic benefit, which resulted in a 12% and 17% relative risk reductions in DM and non-DM patients, respectively, was not as marked as that observed with prasugrel.8,9 In fact, prasugrel therapy had notably high absolute reductions in ischemic events among DM patients in comparison with non-DM patients (DM, 4.8%; non-DM, 1.4%), which led to a 30% and 14% relative risk reductions in DM and non-DM patients, respectively.8,9 However, it is important to emphasize that such comparisons need to be interpreted with great caution given the broad differences between these studies. Nevertheless, these observations have questioned whether prasugrel and ticagrelor have different PD profiles in DM patients. However, comparative PD assessments between these 2 agents, selectively and comprehensively determined in DM patients to rule out potential differences, remained poorly explored until this investigation. Although DM patients have reduced generation of active metabolite and lower platelet inhibition than non-DM patients even when treated with prasugrel,7 the OPTIMUS-3 study showed that standard-dose prasugrel was able to achieve greater platelet inhibition than a double dose of clopidogrel in DM patients.15 Although no investigation has compared the PD effects of clopidogrel and ticagrelor specifically in patients with DM, a subgroup analysis of a randomized study showed that the superior PD efficacy of ticagrelor was consistent in DM patients.25 Indeed, our PD findings do not support a particular benefit in DM patients for prasugrel in comparison with ticagrelor.
Several studies have evaluated the comparative PD effectiveness of prasugrel and ticagrelor in different clinical settings. Results were not consistent across studies, with some studies showing PD equipoise between the 2 agents and others showing more potent effects with ticagrelor.26,27 Nonetheless, data in patients with DM, who are characterized by a unique prothrombotic milieu, are still limited. A study by Laine et al28 assessing the acute effects of ticagrelor versus prasugrel in DM patients showed that ticagrelor was associated with lower PRI levels measured by VASP (6–18 hours after LD). A study by Alexopoulos et al29 assessing the chronic effects of these agents in DM patients showed that ticagrelor was associated with lower PRU levels measured by VN-P2Y12 (2–4 hours after MD). However, both studies did not show any differences in HPR rates.28,29 Indeed, our study results showing that prasugrel and ticagrelor reach overall nonsignificantly different levels of platelet inhibition in both the acute and chronic phases of treatment did not completely confirm these findings. This may be attributed to some methodological differences of these studies, such as the use of a single PD assay, the lack of double blinding, and the lack of evaluation of both the acute and maintenance phases of therapy. In our investigation, 4 different PD assays were used and performed at several time points to evaluate the PD effects of both the LD and MD regimens. Although our VN-P2Y12 data confirmed a difference in 1-week platelet reactivity and a trend toward lower PRU at 2 hours with ticagrelor, this may be attributable to assay-specific issues. In fact, no signal of reduced platelet reactivity with ticagrelor was shown with any of the 3 other assays, including LTA, which still represents the gold standard to measure platelet aggregation, or VASP, which is the most specific technique to evaluate P2Y12 receptor blockade, is not affected by aspirin, and does not take into account P2Y1 receptor activity.30 Moreover, given the pharmacological differences between these agents, with prasugrel an irreversible agent with once daily administration and ticagrelor a reversible agent with twice daily administration, in our study, PD assessments were conducted at very specific time points with relationship to timing of drug intake to enable an accurate comparative assessment.
The P2Y12 receptor signaling pathway plays a central role in atherothrombotic processes by amplifying platelet activation mediated by other receptors.5 This may explain why in vitro studies have shown that prasugrel and ticagrelor are effective in inhibiting markers of ADP- and non–ADP-induced platelet reactivity. In particular, the level of platelet inhibition achieved by combining aspirin and a potent P2Y12 receptor antagonist is no greater than that produced by the P2Y12 receptor antagonist alone.31 Our study confirms these in vitro findings by demonstrating in vivo that potent P2Y12 receptor blockade with both prasugrel and ticagrelor is also associated with inhibitory effects on measures of non–ADP-induced platelet reactivity. In particular, our study further expands on previous observations showing that, in DM patients, the addition of either prasugrel or ticagrelor on top of aspirin is able to significantly reduce thromboxane A2–mediated platelet reactivity, as assessed by assays sensitive to aspirin-induced effects (arachidonic acid- and collagen-induced aggregation), and platelet reactivity mediated by thrombin, as well, in both the acute and maintenance phases of treatment. These novel in vivo findings can indeed contribute to the enhanced antiplatelet efficacy of these agents, which may be noteworthy in patients with DM, given their upregulation of various platelet signaling pathways. In fact, recent data from the PEGASUS-TIMI 54 trial (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), a secondary prevention study conducted in patients who experienced a prior (1–3 years) myocardial infarction, showed that prolonged treatment with ticagrelor, on a background of aspirin therapy, was associated with a reduction in mortality in patients with DM, albeit at the expense of increased bleeding.32 Although the PD substudy of this trial showed no effect of ticagrelor on the measurements of aspirin response, only 28% of patients had DM.33 Additional insights on the clinical implications of ticagrelor therapy in DM patients will derive from the ongoing THEMIS study (Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study; NCT01991795), which is being conducted selectively in DM patients with documented CAD but without myocardial infarction. Ultimately, the PD findings from our study, along with previous investigations, support the central role of the P2Y12 receptor on amplifying platelet reactivity mediated by other signaling pathways by showing platelet inhibitory effects on various measures of platelet reactivity, including ADP- and non–ADP-induced. Such more comprehensive platelet inhibitory effect has questioned the need for long-term aspirin therapy in patients undergoing percutaneous coronary intervention when treated with more potent P2Y12 receptor blockade. Dropping aspirin therapy as a strategy to reduce bleeding complications without any trade-off in efficacy among patients treated with potent oral P2Y12 receptor inhibitors is currently being tested in several clinical trials, including in patients undergoing percutaneous coronary intervention (NCT02270242, NCT01813435).
Study Limitations
Our study was conducted using standard dosing regimens of prasugrel (60 mg LD/10 mg MD) and ticagrelor (180 mg LD and 90 mg twice daily MD) in patients with stable CAD, and it is unknown if our observations can be generalized to patients experiencing an acute coronary event. However, it would have been unethical to conduct a crossover study with a wash-out period in these patients who require dual-antiplatelet therapy. Moreover, our results cannot be extrapolated to lower dosing regimens of prasugrel (ie, 5 mg) and ticagrelor (ie, 60 mg). In our study, the PD effect of the LD was assessed 2 hours postdosing. Indeed, additional time points after LD would have allowed us to better define timing of peak platelet inhibitory effects. Our in vivo findings on the impact of more potent P2Y12 receptor blockade on measures of non–ADP-induced platelet reactivity cannot be extrapolated to non-DM patients who do not have heightened platelet reactivity, which would perhaps not allow to unravel such a treatment effect. Moreover, markers of non–ADP-induced platelet reactivity were measured only by a single assay. Ultimately, our study was not powered for safety or efficacy; thus, no conclusions on the clinical comparisons between prasugrel and ticagrelor can be drawn, which is currently being investigated in an ongoing clinical trial.34
Conclusions
In DM patients with CAD, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity than prasugrel in the acute and chronic phases of treatment, whereas markers of non–ADP-induced please reactivity were not significantly different between the 2 agents. Such similar PD profiles translate into similarly low rates of HPR, a marker of risk for atherothrombotic recurrences. Results of ongoing clinical trials will provide further details on the role of potent P2Y12 receptor inhibition in DM patients with CAD.
Acknowledgments
Drs Franchi and Rollini performed statistical analysis; Dr Angiolillo handled funding and supervision; Dr Franchi and Latonya Been acquired the data; Drs Angiolillo, Rollini, and Franchi conceived and designed the research; Drs Franchi, Rollini, and Angiolillo drafted the manuscript; Drs Aggarwal, Hu, Kureti, Durairaj, Duarte, and Cho, Latonya Been, and Drs Zenni and Bass made critical revision of the manuscript for key intellectual content.
Sources of Funding
This work was supported by an institutional grant of the University of Florida College of Medicine-Jacksonville.
Disclosures
Dr Angiolillo has received payment as an individual for: (a) consulting fees or honoraria from Sanofi, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, Amgen, Bayer, Pfizer, and PLx Pharma; (b) participation in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical. Institutional payments for grants received from Glaxo-Smith-Kline, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead. The other authors have no conflicts of interest to disclose.
Footnotes
Sources of Funding, see page 790
The online-only Data Supplement, podcast, and transcript are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.116.023402/-/DC1.
Circulation is available at http://circ.ahajournals.org.
- Received May 9, 2016.
- Accepted July 5, 2016.
- © 2016 American Heart Association, Inc.
References
Clinical Perspective
What Is New?
In patients with diabetes mellitus and coronary artery disease on low-dose aspirin therapy, ticagrelor and prasugrel are associated with potent platelet inhibitory effects, with ticagrelor therapy associated with similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment.
In addition to their potent inhibitory effects on ADP-induced platelet reactivity, both agents significantly reduce measures of non–ADP-induced, including thromboxane-, collagen-, and thrombin-activated, platelet reactivity.
What Are the Clinical Implications?
Although observations from clinical trials have led to questions of whether prasugrel and ticagrelor have different beneficial profiles, overall our pharmacodynamic findings do not support a particular advantage of 1 agent over the other in patients with diabetes mellitus.
Therefore, the choice of therapy should take into consideration other aspects, including patient management (eg, invasive versus noninvasive management) and the presence of contraindications (eg, previous cerebrovascular event), which may favor the use of 1 drug compared with another.
Prasugrel and ticagrelor also are associated with inhibitory effects on multiple markers of non–ADP-induced platelet reactivity, which can contribute to their antithrombotic efficacy and may be noteworthy in patients with diabetes mellitus given their enhanced prothrombotic profile.
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