Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects

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1 Journal of Thrombosis and Haemostasis, 12: DOI: /jth ORIGINAL ARTICLE Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects S. WEISSHAAR,* B. LITSCHAUER,* G. GOUYA,* P. MAYER,* L. SMERDA,* S. KAPIOTIS, P. A. KYRLE, S. EICHINGER and M. W O L Z T * *Department of Clinical Pharmacology, Medical University of Vienna; Clinical Institute of Medical and Chemical Laboratory Diagnostic, Medical University of Vienna; and Division of Haematology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria To cite this article: Weisshaar S, Litschauer B, Gouya G, Mayer P, Smerda L, Kapiotis S, Kyrle PA, Eichinger S, Wolzt M. Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects. J Thromb Haemost 2014; 12: Summary. Background: Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature. Methods and Results: Platelet activation (b-thromboglobulin [b-tg]) and thrombin generation (prothrombin fragment [F 1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR ). Coagulation biomarkers in shed blood were assessed at 3 h monotherapy with the medicines under study, at 3 h triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood b-tg and were more pronounced than phenprocoumon at an INR of In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of b-tg, F 1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough Correspondence: Michael Wolzt, Department of Clinical Pharmacology, Medical University of Vienna, W ahringer G urtel 18-20, A-1090 Vienna, Austria. Tel.: ; fax: Received 27 May 2014 Manuscript handled by: M. Levi Final decision: F. R. Rosendaal, 7 September 2014 steady state. Conclusion: A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo. Keywords: aspirin; dabigatran; drug therapy, combination; phenprocoumon; rivaroxaban; ticagrelor. Introduction The acute coronary syndrome (ACS) is a serious complication of atherosclerosis that is associated with significant mortality and morbidity [1]. Dual antiplatelet therapy (DAPT) comprising acetylsalicylic acid (ASA) and a P2Y 12 receptor antagonist such as clopidogrel, prasugrel or ticagrelor has become standard treatment for cardiac patients undergoing percutaneous coronary intervention (PCI) to prevent a major adverse cardiac outcome [2 4]. The reversible third-generation P2Y 12 antagonist ticagrelor has been shown to reduce the rate of coronary stent thrombosis [5]. Ticagrelor is also considered to be superior to clopidogrel in reducing the combined endpoint of cardiovascular death, myocardial infarction or stroke, with similar rates of overall major bleeding [6]. Atrial fibrillation (AF) is the most common sustained arrhythmia and requires long-term treatment with oral vitamin K antagonists (VKAs) or novel oral anticoagulants (NOACs) targeting specific enzymes of the coagulation pathway, such as the direct factor Xa (FXa) inhibitor rivaroxaban or the direct thrombin inhibitor (DTI) dabigatran. NOACs have demonstrated a superior risk/benefit profile compared with VKAs for several indications [7 10]. Up to 30% of AF patients have concomitant coronary artery disease (CAD) and may require acute or elective

2 Antithrombotic triple therapy 1851 coronary stenting [11]. This high-risk population may benefit from intermittent antithrombotic triple therapy coronary intervention [12]. Available clinical evidence is mostly based on retrospective observational studies or registry data, except for one randomized prospective trial [13 19]. Current guidelines suggest triple therapy with clopidogrel + ASA + VKA for a period ranging from 4 weeks up to 6 months [20 22]. At present, triple therapy with other antithrombotic drugs is not recommended due to a paucity of data investigating NOACs combined with newer and more effective P2Y 12 antagonists [2,4]. The importance of prospective trials to elucidate this challenging clinical issue, particularly with combinations of modern anticoagulants, has been addressed recently [23]. The shed blood technique allows for the investigation of coagulation activation at the site of plug formation in vivo by assessing markers of thrombin generation and platelet activation. It involves collection of blood emerging from standardized incisions of the skin microvasculature. This model has been used previously to study the impact of various anticoagulants at different doses on thrombin generation and platelet activation under physiologic conditions [24 31]. The aim of this study was to assess the effect of orally administered ticagrelor and ASA in combination with dabigatran, rivaroxaban or phenprocoumon at pharmacokinetic steady state conditions on hemostatic system inhibition in healthy subjects. Methods The study protocol was approved by the Ethics Committee of the Medical University of Vienna, Austria (EK1302/2012), and the national Competent Authority. It complies with the Declaration of Helsinki, including current revisions, and the ICH Good Clinical Practice Guidelines. The trial is registered at ClinicalTrials.gov (NCT ) and at the European Clinical Trials database (EudraCT ). All subjects gave written informed consent to participate before any study-specific procedure was applied. Study population In total, 84 healthy male volunteers meeting the inclusion criteria of non-smoking, age years and body mass index (BMI) of kg m 2 were screened to randomize 60 subjects (Fig. 1). Exclusion criteria included any significant physical or laboratory finding; a significant history of renal, hepatic, gastrointestinal or cardiac disease; disorders with an increased risk of bleeding or coagulation diseases; use of any medication within 2 weeks before the screening examination that was performed 3 14 days before the first study day. Alcohol consumption was not allowed during the study. Due to ethical concerns this study was conducted in healthy subjects rather than in AF patients with ACS to avoid a discontinuation of preexisting antithrombotic treatment. Study design & study drugs This single-center, prospective, randomized, controlled, analyst-blinded, parallel group study was conducted between October 2012 and July 2013 at the Department of Clinical Pharmacology, Medical University of Vienna, Austria. Subjects were allocated according to a predefined randomization code obtained from a web-based application to one of three treatment groups (A, B or C; n = 20 per group; Fig. 1) to receive ticagrelor (Brilique â ; Astra Zeneca AB, S odert alje, Sweden) + ASA (Thrombo ASS â ; Lannacher Heilmittel GmbH, Lannach, Austria) in combination with dabigatran (Pradaxa â ; Boehringer Ingelheim International, Ingelheim am Rhein, Germany; A) or rivaroxaban (Xarelto â ; Bayer Schering Pharma, Berlin, Germany; B) or phenprocoumon (Marcoumar â ; Meda Pharma GmbH, Vienna, Austria; C) for 5 days to ensure steady state conditions and an International Normalized Ratio (INR) of (C). Phenprocoumon dosing was prolonged if an INR of could not be reached within the time period foreseen. Additionally, the effect of ticagrelor, dabigatran, rivaroxaban and phenprocoumon was assessed separately. In the first investigational period, subjects received a single dose of 150 mg dabigatran (A), a single dose of 20 mg rivaroxaban (B) or 9 mg phenprocoumon once daily (od) for 3 days (C) titrated on the following days to reach an INR of within 4 days. INR was assessed from whole blood using a point of care device (Coagu- Chek â XS; Roche Diagnostics GmbH, Mannheim, Germany). After a washout period of at least 1 week (A, B) or until INR was 1.2 (C) a loading dose of 180 mg ticagrelor was administered in the second investigational period to all study participants. Twenty-four hours the loading dose, ticagrelor 90 mg was given twice daily (bid) with ASA (300 mg loading dose followed by 100 mg od) together with 150 mg dabigatran bid (A) or 20 mg rivaroxaban od (B) or INR-adjusted phenprocoumon (C) over 5 consecutive days. An end-of-study examination was performed 1 week the last intake of medicine. Study objectives The primary study endpoint was to compare changes from baseline and between groups in the main outcome parameter, shed blood b-thromboglobulin (b-tg), a marker of platelet activation, during a single treatment with the medicines under investigation and during different triple therapy regimens. Secondary objectives included assessment of the thrombin generation markers prothrombin fragment (F 1+2 ) and thrombin-antithrombin complex (TAT) in shed blood at these time-points. b-tg is a protein released by platelet granules during activation

3 1852 S. Weisshaar et al 24 drop outs: - Withdrawal of consent (n = 7) - Abnormal laboratory finding (n = 16) - Arterial hypertension (n = 1) 84 subjects assessed for eligibility 60 randomized (n = 20 per group) A B C 1st investigational period 150 mg dabigatran SD 20 mg rivaroxaban SD Phenprocoumon at INR 2 3 wash out period 180 mg ticagrelor LD 180 mg ticagrelor LD 180 mg ticagrelor LD 2nd investigational period [32]. F 1+2 is a peptide truncated from prothrombin during its conversion to thrombin by the prothrombinase complex, which is assembled by factor Xa and co-factor Va on membrane surfaces [33]. TAT is formed when thrombin cleaves a scissile bond of antithrombin III [34]. b-tg was considered as the primary outcome parameter because previous studies [25,26] have shown that OAC decreased similarly b-tg and thrombin generation markers and a major effect of ticagrelor on F 1+2 or TAT was not expected. Other secondary objectives included pharmacokinetics of ticagrelor, dabigatran and rivaroxaban, shed blood volume, the concentration of activation markers in venous blood and safety. Blood sampling 300 mg ASA 150 mg dabigatran bid 100 mg ASA od 150 mg dabigatran bid Shed blood Shed blood was obtained in the first study period pre-dose and 3 h single doses of dabigatran or rivaroxaban or at an INR of when phenprocoumon was administered. In the second period, shed blood was collected at baseline and 3 and 24 h ticagrelor loading, 3 h triple therapy with dabigatran or rivaroxaban and at trough steady state immediately before the next drug administration would have been due. Collections were performed as described previously [35] with minor adaptations. A sphygmanometer cuff was placed on the upper arm and inflated to 45 mmhg. Two incisions, 5 mm long and 1 mm deep, were placed on the lateral aspect of the forearm parallel to the antecubital crease by using disposable standard bleeding time devices 300 mg ASA 20 mg rivaroxaban od 100 mg ASA od 20 mg rivaroxaban od 300 mg ASA Phenprocoumon at INR mg ASA od Phenprocoumon at INR 2 3 Fig. 1. Study flow chart. SD, single dose; LD, loading dose; od, once daily; bid, twice daily; INR, international normalized ratio; ASA, acetylsalicylic acid. (Surgicutt â ; ITC, Edison, NJ, USA). In order to avoid activation of platelets and coagulation factors due to skin contact, shed blood was collected directly from the edge of the skin at 15-s intervals over a period of 4 min using plastic pipette tips (Greiner Bio One International AG, Kremsm unster, Austria) and no additional manoeuvre applied. Four minutes of sampling was chosen because it has been demonstrated that shed blood markers reach plateau levels within this period [36]. The blood from each incision site was transferred immediately into separate ice-cooled plastic tubes containing 100 ll stop solution (3.8% sodium citrate, 0.5% indomethacin dissolved with ethanol, 10% aprotinin [400 lmol L 1 ]) to prevent further thrombin generation or platelet activation in the tubes. Bleeding time incision experiments were performed by the same investigator throughout the entire study to reduce operator variability. Shed blood volume per incision was estimated from pre- and post-sampling tube weights and total shed blood volume was calculated. The test tubes were immediately centrifuged at g for 10 min at 4 C. The plasma was separated, pooled, and stored at 80 C until analysis. b-tg, F 1+2 and TAT plasma concentrations in shed blood were determined by adjustment of ELISA readings with a correction factor calculated from the ratio of stop solution to individual shed blood in the collection tubes: correction factor = (stop solution in both tubes [200 ll]/total shed blood volume [ll]) + 1. Venous blood Blood for venous b-tg, F 1+2, TAT and anti-xa activity (only B) was collected by fresh Day 1 Day 2 5 Triple therapy for 5 days

4 Antithrombotic triple therapy 1853 venepunctures without tourniquet at pre-dose, 3 h single dosing, 3 and 24 h post-ticagrelor loading (except for anti-xa activity), 3 h triple therapy start and at steady state at expected trough levels (at 12 h for ticagrelor and dabigatran bid dosing and 24 h for ASA, rivaroxaban and phenprocoumon od dosing) and/or at an INR of (C). Blood samples for b-tg were collected in CTAD tubes (Greiner Bio One International AG); for F 1+2, TAT and anti-xa activity 3.8% sodium citrate tubes (Greiner Bio One International AG) were used. Dabigatran levels were assessed in group A at pre-dose, 3 h post-single and post-triple therapy dosing and at steady state trough levels. Blood samples for ticagrelor plasma concentrations and its active metabolite AR- C124910XX were taken pre-dose, 3 and 24 h post-ticagrelor loading, 3 h triple therapy and at steady state 12 h last ticagrelor intake. Blood for pharmacokinetic analysis was drawn into tubes containing EDTA (Greiner Bio One International AG). Instead of rivaroxaban plasma levels, anti-xa activity calibrated for rivaroxaban was assessed in treatment group B [37]. All venous blood samples were centrifuged at g for 15 min at 4 C. The separated plasma was stored at 80 C until analysis. Bioanalytical assessment Laboratory analysis was performed according to standard procedures at the Clinical Institute of Laboratory Medicine, General Hospital Vienna, Austria, except for the following: the ASSERACHROM â b-tg test kit (Diagnostica Stago, Asnieres, France) was used for b-tg assessment, F 1+2 concentrations were determined by the Enzygnost â F 1+2 microtest kit (Dade Behring GmbH, Marburg, Germany) and TAT was assessed using the Enzygnost â TAT micro kit (Siemens GmbH, Munich, Germany). The lower limits of quantifications (LLQ) for the assays were 12 and 120 IU ml 1 (venous and shed blood, respectively) for b-tg, 20 and 500 pmol L 1 for F 1+2, and 2 and 20 lg L 1 for TAT, respectively. Shed blood LLQ resulted from dilution of shed blood samples (b-tg, TAT [1 : 10]; F 1+2 [1 : 25]). Samples for pharmacokinetic parameters were prepared by liquid-liquid extraction (dabigatran) and protein precipitation (ticagrelor, AR-C124910XX). Plasma dabigatran concentrations were measured at menal GmbH (Emmendingen, Germany); ticagrelor and AR- C124910XX assessment was performed at Covance Bioanalytical Services, LLC (Indianapolis, IN, USA) using validated LC-MS/MS methods. The detection ranges were ng ml 1 for dabigatran, nmol L 1 for ticagrelor and nmol L 1 for AR-C124910XX. Rivaroxaban levels were measured as anti-xa activity with an ACL TOP500 coagulation analyser (Instrumentation Laboratory, Vienna, Austria) using rivaroxaban as assay standard (LLQ < 14 ng ml 1 ). Statistical analysis and sample size Statistical analysis was performed using SPSS 21.0 for Macintosh (IBM Cooperation, New York, NY, USA). Data were analyzed descriptively and the results are expressed as median and range. The Kruskal Wallis test was used to compare demographic and screening laboratory characteristics. b-tg, F 1+2, TAT and shed blood volume data were transformed logarithmically to obtain normal distributions. A repeated measures analysis of variance (ANOVA) was performed to test for effect of treatment using the time-point as within-subject factor and treatment as between factor grouping variable. If a significant interaction between group and time-point was detected, post hoc comparisons of the absolute change from baseline of b-tg, F 1+2 or TAT concentrations were made applying unpaired t-tests. Alpha level adjustment for six comparisons within the study cohort for the primary outcome parameter, shed blood b-tg, was performed based on a Bonferroni correction. A two-tailed P value of was calculated to be statistically significant for b-tg. No adjustment for multiple comparisons was applied to secondary (shed blood) outcome parameters. Thus, a P value < 0.05 was considered to indicate statistical significance. Sample size was determined from the per cent change in the main outcome parameter, shed blood b-tg, assuming a within-group standard deviation of 21% based on a previous trial with a comparable study cohort [26]. A sample size of 20 subjects per group was calculated to have 80% power to detect a difference in means of 20% between treatment groups, using a two-sample t-test with a two-sided significance level of This sample size also considered drop-out of two subjects. Table 1 Demographic data and laboratory characteristics of randomized study participants Age (years) 24 (19 35) 24 (20 36) 25 (19 30) Body mass index (kg m 2 ) 23.4 ( ) 22.7 ( ) 23.0 ( ) Platelet count (G L 1 ) 240 ( ) 220 ( ) 241 ( ) Prothrombin time (%) 101 (76 141) 100 (77 116) 104 (78 122) Activated partial thromboplastin time (s) 33.7 ( ) 34.4 ( ) 35 (31 41) Serum creatinine (mg dl 1 ) 0.88 ( ) 0.92 ( ) 0.89 ( ) Aspartate aminotransferase (U L 1 ) 25 (14 59) 26 (17 43) 25 (15 53) Alanine aminotransferase (U L 1 ) 30 (18 130) 25 (15 42) 22 (9 61) c-glutamyl transferase (U L 1 ) 17 (13 59) 19 (10 52) 18 (13 40) Data are presented as median and range (n = 20 per group).

5 1854 S. Weisshaar et al Results Subject demographics Demographic and laboratory characteristics of randomized subjects are presented in Table 1 and did not differ between treatment groups (P > 0.05 for all parameters, Kruskal Wallis test). Ticagrelor, dabigatran and rivaroxaban pharmacokinetics, phenprocoumon pharmacodynamics There was a linear correlation between ticagrelor plasma concentrations and its active metabolite AR-C124910XX with a correlation coefficient q = 0.99 (P < 0.001). Combined ticagrelor + AR-C124910XX concentrations, dabigatran and rivaroxaban (measured as anti-xa activity with rivaroxaban as calibrator) concentrations at corresponding time-points and groups are summarized in Table 2. In subjects receiving phenprocoumon a median interval of 5 days (range: [4 7] first study period; [5 8] second study period) was required to reach the target INR. INRs at corresponding time-points are presented in Table 2. Effect on coagulation activation markers Pre-dose (baseline) shed blood b-tg, F 1+2, TAT and volume were comparable between study groups (P > 0.05 for all parameters, ANOVA). In contrast, venous baseline levels varied substantially across groups, which is consistent with previous studies [25,26]. Thus, further analysis of venous outcome parameters was not performed. Individual concentrations of shed blood markers within different study cohorts and b-tg, F 1+2 and TAT vs. dabigatran or rivaroxaban concentrations are provided in the online supplemental material (Figures S1 S5). Shed blood b-tg Data are summarized in Table 3. Administration of dabigatran, rivaroxaban, phenprocoumon or ticagrelor alone significantly decreased shed blood b-tg across all treatment groups compared with individual pre-dose concentrations (P < 0.001, ANOVA). Following single doses of dabigatran or rivaroxaban b-tg was significantly lower at 3 h administration as compared with phenprocoumon at INR (45%, 37% and 18% below baseline, respectively; P < A vs. C and P = B vs. C, post hoc t-test; Fig. 2). After ticagrelor loading (absence of combination treatment), median b-tg dropped to 47% (A), 42% (B) and 53% (C) below baseline at 3 h post-dosing. Twenty-four hours loading, b-tg concentrations almost re-established but remained statistically significantly below pre-dose concentrations (15% [A], 28% [B] and 32% [C]), with a trend to higher levels in group A vs. group C (P = 0.05, post hoc t test). This may be due to between-subject differences in pharmacokinetics, which resulted in approximately 17% lower ticagrelor + AR-C124910XX concentrations. Further, the moderate correlation coefficient of q = 0.42 (P < 0.001) between ticagrelor + AR-C124910XX and b-tg may explain this finding. The maximum decrease of b-tg occurred at 3 h triple therapy initiation, when b-tg fell by 78% (A) and 80% (B) below pre-dose levels. At steady state Table 2 Pharmacokinetics of the sum of ticagrelor + AR-C124910XX (upper panel), dabigatran and rivaroxaban plasma concentrations (measured as anti-xa activity with rivaroxaban as calibrator) and pharmacodynamics of phenprocoumon (lower panel) Ticagrelor + AR-C124910XX (nmol L 1 ) Baseline n.a. n.a. n.a. 3 h single dose/inr 2 3 n.a. n.a. n.a. Baseline < LOQ < LOQ < LOQ 3 h ticagrelor loading 1861 ( ) 1741 ( ) 1937 ( ) 24 h ticagrelor loading 124 (50 658) 150 (96 674) 150 (62 377) 3 h triple therapy 1078 ( ) 1010 ( ) n.a. Steady state (trough) 553 ( ) 651 ( ) 589 ( ) Dabigatran Rivaroxaban International (ng ml 1 ) (ng ml 1 ) Normalized Ratio Baseline < 1.6 < ( ) 3 h single dose/inr (19 143) 133 (39 317) 2.3 ( ) Baseline < 1.6 < ( ) 3 h ticagrelor loading n.a. n.a. n.a. 24 h ticagrelor loading n.a. n.a. n.a. 3 h triple therapy 104 (37 211) 223 (98 312) n.a. Steady state (trough) 53 (18 81) 23 (< ) 2.3 ( ) Data are presented as median and range (n = 20 per group). n.a., not assessed; LOQ, limit of quantification.

6 Antithrombotic triple therapy 1855 Table 3 Shed blood b-thromboglobulin (b-tg), prothrombin fragment 1 + 2(F 1+2 ) and thrombin-antithrombin complex (TAT) concentrations (n = 20 per group) Shed blood b -TG (IU ml 1 ) Baseline 2079 ( ) 1534 ( ) 1741 ( ) 3 h single dose/inr ( ) 987 ( ) 1434 ( )* (A,B) Baseline 1819 ( ) 1714 ( ) 1569 ( ) 3 h ticagrelor loading 956 ( ) 987 ( ) 744 ( ) 24 h ticagrelor loading 1540 ( ) 1248 ( ) 1065 ( ) 3 h triple therapy 405 ( ) 351 ( ) n.a. Steady state (trough) 541 ( ) 675 ( ) 554 ( ) Shed blood F 1+2 (pmol L 1 ) Baseline 3385 ( ) 3291 ( ) 3099 ( ) 3 h single dose/inr ( )* (B,C) 1631 ( ) 1721 ( ) Baseline 3193 ( ) 3183 ( ) 2637 ( ) 3 h ticagrelor loading 2897 ( ) 3086 ( ) 2939 ( ) 24 h ticagrelor loading 3173 ( ) 2906 ( ) 3061 ( ) 3 h triple therapy 2031 ( ) 1531 (< ) n.a. Steady state (trough) 2607 ( ) 2675 ( ) 1632 ( ) Shed blood TAT (lg L 1 ) Baseline 578 ( ) 494 ( ) 509 ( ) 3 h single dose/inr ( )* (B,C) 158 (< ) 293 (68 546)* (B) Baseline 570 ( ) 630 ( ) 510 ( ) 3 h ticagrelor loading 661 ( ) 550 ( ) 539 ( ) 24 h ticagrelor loading 584 ( ) 545 ( ) 507 ( ) 3 h triple therapy 383 ( )* (B) 127 (31 325) n.a. Steady state (trough) 387 ( ) 410 (< ) 237 (38 424) Data are presented as median and range. *(group) P < for absolute changes between groups (post hoc t-test); P compared with baseline (ANOVA for repeated measures). n.a., not assessed. Shed blood β-tg [IU ml 1 ] Dabigatran (A) Rivaroxaban (B) Phenprocoumon (C) * (A,B) trough conditions b-tg remained suppressed across treatment groups, with median reductions from baseline of 71% (A), 61% (B) and 65% (C). Shed blood F 1+2 BL 3 h BL 3 h 24 h 3 h ticagrelor ticagrelor LD LD SD or at target INR triple therapy dosing Steady state (trough) Fig. 2. Shed blood b-thromboglobulin (b-tg) concentrations by treatment group and time-point. Data are presented as median (95% confidence interval). *(group) P < for absolute changes between groups. BL, baseline; SD, single dose; INR, international normalized ratio; LD, loading dose (n = 20 per group). Data are summarized in Table 3. In the first investigational period, single doses of rivaroxaban or phenprocoumon titrated to INR induced similar reductions in shed blood F 1+2 (50% and 45% below baseline, respectively), which were significantly higher as compared with dabigatran alone, where F 1+2 remained unchanged (P < A vs. B/C, post hoc t-test; Fig. 3). Ticagrelor loading did not affect thrombin generation at 3 and 24 h post-dosing. Triple therapy reduced F 1+2 at 3 h post-dosing and at trough steady state compared with baseline across all groups (P < 0.001, ANOVA). At 3 h initiation of triple therapy, shed blood F 1+2 formation decreased to 36% below baseline with dabigatran and to 52% below pre-dose concentration with rivaroxaban. A trend towards different F 1+2 concentrations at 3 h triple therapy between groups was observed (P = 0.053,

7 1856 S. Weisshaar et al 5000 Dabigatran (A) Rivaroxaban (B) Phenprocoumon (C) 1000 Dabigatran (A) Rivaroxaban (B) Phenprocoumon (C) Shed blood F1+2 [pmol L 1 ] * (B,C) Shed blood TAT [μg L 1 ] * (B,C) * (B) * (B) 0 post hoc t-test; dabigatran vs. rivaroxaban). At trough steady state F 1+2 levels remained at 18% (A) and 16% (B) below pre-dose concentrations. Triple therapy with phenprocoumon reduced shed blood F 1+2 formation similarly to dabigatran or rivaroxaban at trough steady state. Shed blood TAT BL 3 h BL 3 h 24 h 3 h ticagrelor ticagrelor LD LD SD or at target INR tripple therapy dosing Steady state (trough) Fig. 3. Shed blood prothrombin fragment 1 + 2(F 1+2 ) concentrations by treatment group and time-point. Data are presented as median (95% confidence interval). *(group) P < for absolute changes between groups. BL, baseline; SD, single dose; INR, international normalized ratio; LD, loading dose (n = 20 per group). Data are summarized in Table 3 and Fig. 4. Single doses of dabigatran or rivaroxaban at 3 h or phenprocoumon at an INR significantly reduced shed blood TAT levels (17%, 68% and 42% below pre-dose, respectively; P < 0.001, ANOVA). Rivaroxaban and phenprocoumon caused significantly higher TAT reductions as compared with dabigatran (P < A vs. B; P = A vs. C, post hoc t-test) and TAT had a more pronounced decrease in response to rivaroxaban than phenprocoumon (P = 0.001, post hoc t-test). Similar to F 1+2, TAT formation was unaffected at 3 and 24 h ticagrelor loading in the second investigational period. During triple therapy, TAT significantly decreased across all treatment groups at 3 h and at trough steady state as compared with baseline (P < 0.001, ANOVA). A triple therapy with rivaroxaban at 3 h post-dosing induced significantly greater TAT reductions than with dabigatran (80% vs. 32%; P < 0.001, post hoc t-test). At trough steady state the effect on TAT was similar across groups ) in the three treatment groups. Increases in shed blood volume were noted drug administration at all time-points, with peak values ranging from % over baseline at 3 h ticagrelor loading and % at steady state during triple therapy. No significant changes in shed blood volume between groups and corresponding time points were detected. Adverse events Forty-two adverse events were recorded. These were reported as mild or moderate in intensity and resolved without any intervention. Of these, 24 adverse events were not related to the study drugs and 18 were attributed to the investigational products and occurred only during triple therapy (group A, n = 1; B, n = 11; C, n = 6) and not when OACs were administered alone. Epistaxis (n = 9) was the most common event, followed by gastrointestinal discomfort drug intake (n = 3), gingival bleeding (n = 2), petechiae of the lower limb (n = 1), extensive hematoma (n = 1), hemorrhoidal bleeding (n = 1) and prolonged bleeding from the shed blood incision site (n = 1) BL 3 h SD or at target INR BL 3 h ticagrelor LD 24 h ticagrelor LD 3 h tripple therapy dosing Steady state (trough) Fig. 4. Shed blood thrombin-antithrombin complex (TAT) concentrations by treatment group and time-point. Data are presented as median (95% confidence interval). *(group) P < for absolute changes between groups. BL, baseline; SD, single dose; INR, international normalized ratio; LD, loading dose (n = 20 per group). Shed blood volume Data are presented in Table 4. Median shed blood volumes at baseline were between 143 and 176 ll (range, Discussion This randomized, controlled trial shows that DAPT comprising ASA and ticagrelor in combination with

8 Antithrombotic triple therapy 1857 Table 4 Total shed blood volume (n = 20 per group) Shed blood volume (ll) Baseline 170 (57 476) 152 (39 238) 156 (79 336) 3 h single dose/inr (43 492) 211 (55 364) 200 (81 511) Baseline 176 (56 396) 143 (56 367) 172 (49 389) 3 h ticagrelor loading 294 ( )* 261 ( )* 269 ( )* 24 h ticagrelor loading 233 (24 879) 214 (79 523) 217 ( ) 3 h triple therapy 267 (81 503)* 238 (82 649)* n.a. Steady state (trough) 251 ( )* 266 ( )* 269 ( )* Data are presented as median and range. *P and P compared with baseline (ANOVA for repeated measures). n.a., not assessed. dabigatran or rivaroxaban or phenprocoumon effectively attenuates hemostatic system activation in shed blood in healthy subjects. This is reflected by an inhibition of both platelet activation (b-tg) and thrombin generation (F 1+2, TAT) at steady state conditions. Inhibition of b-tg release was more pronounced single doses of dabigatran, rivaroxaban or ticagrelor than with phenprocoumon at INR A single rivaroxaban dose reduced thrombin generation more than dabigatran or phenprocoumon. Shed blood reflects activation of microvasculature coagulation at the site of plug formation in vivo [28]. In contrast to in vitro laboratory tests where the coagulation system is in a resting state, this model enables the assessment of antithrombotic drug pharmacodynamics under activated conditions [25,26]. However, shed blood markers act as surrogates and cannot be used to predict the risk of bleeding or thromboembolic events. Likewise, shed blood volume should be interpreted cautiously as it is subject to substantial variability across the study cohorts and does not represent clinical bleeds. Our data suggest that the different triple therapy combinations under investigation are equally effective at preventing thrombin generation and platelet activation at the site of plug formation. The action of ASA + ticagrelor on b-tg inhibition appears additive to OAC treatment. While ticagrelor is known to decrease platelet reactivity by reversible binding to the P2Y 12 receptor and antagonizing adenosine-diphosphate (ADP)-mediated platelet aggregation, VKAs and NOACs presumably exert their effect on b-tg primarily through attenuation of thrombin-induced platelet activation [38,39]. Interestingly, both NOACs showed a similar effect on platelet inhibition as ticagrelor loading at 3 h post-dosing. This might be of clinical interest in subjects at high risk of bleeding, where NOACs alone could provide effective attenuation of platelet activation. There is evidence that a VKA on top of ASA does not adequately prevent stent thrombosis [40], which is compatible with our finding of a smaller reduction in b-tg during phenprocoumon treatment alone as compared with NOACs or ticagrelor. In this study the effect of ASA alone was not assessed due to the increased complexity of the study design. However, it has been shown previously that ASA does not significantly alter shed blood b-tg and F 1+2 [30]. Thus, the additive effect of DAPT with an OAC is most likely attributable to the presence of ticagrelor. In contrast to ticagrelor 0 s impact on platelet activation, its effect on shed blood thrombin generation was trivial. A single dose of dabigatran significantly reduced TAT but there was little if any effect on shed blood F 1+2, which is at variance with other DTI such as melagatran or hirudin [26,41], suggesting that further thrombin generation by feedback mechanisms was blocked by dabigatran. This is also supported by the marked decrease in b-tg a single dose of dabigatran. However, a reduction of shed blood thrombin generation was only evident at high dabigatran plasma concentrations (Figure S4). This is consistent with data from patients undergoing PCI, where an elevation of venous F 1+2 and TAT was indirectly proportional to the dose of dabigatran administered [42]. We also observed an augmented thrombin generation (F 1+2 > TAT), particularly in some subjects receiving dabigatran (Figures S2 and S3). This is in agreement with recently published data suggesting that low doses of DTI increase F 1+2 and TAT formation [43]. The inhibitory effect of dabigatran on thrombin generation was greater at 3 h dosing with DAPT, when a median dabigatran plasma concentration increase of 230% vs. single-dose levels was detectable. This pharmacokinetic finding might be due to P-glycoprotein inhibition and a drug-drug interaction with ticagrelor [44,45]. Differences in TAT data at 3 h triple therapy may be explained by different dosing intervals of rivaroxaban (od) and dabigatran (bid). The observed lower F 1+2 concentrations at 3 h initiation of triple therapy with rivaroxaban or dabigatran compared with trough steady state conditions is in agreement with the reversible pharmacodynamic action of these NOACs. In contrast, phenprocoumon causes a more uniform inhibition of thrombin formation with less diurnal variability. It is possible that results in subjects with (even mildly) impaired renal or hepatic function might differ from those seen in healthy subjects under study. The betweenand within-subject variability is presumably smaller in our cohort of volunteers compared with elderly patients

9 1858 S. Weisshaar et al with AF and ACS. Moreover, the shed blood model does not mimic the high shear rate conditions of the vascular bed in stenosed arteries where conditions of platelet activation and plasmatic coagulation vary from those of the skin microvasculature. Thus clinical observations are required to confirm our findings of similar antithrombotic efficacy of the drugs under study at steady state. It also remains to be shown whether an acute single dose of a NOAC without concomitant ASA or a reduced dose of ticagrelor can confer a similar benefit during acute coronary intervention with a smaller risk of bleeding compared with current clinical regimens. cohorts (A = dabigatran, B = rivaroxaban, C = phenprocoumon). Fig. S4. Individual shed blood b-thromboglobulin (b-tg) levels (A), prothrombin fragment 1+2 (F 1+2 ) levels (B) and thrombin-antithrombin complex (TAT) levels (C) vs. dabigatran concentrations. Fig. S5. Individual shed blood b-thromboglobulin (b-tg) levels (A), prothrombin fragment 1+2 (F 1+2 ) levels (B) and thrombin-antithrombin complex (TAT) levels (C) vs. rivaroxaban concentrations (measured as anti-xa activity with rivaroxaban as calibrator). Conclusion A triple therapy of ticagrelor and ASA in combination with dabigatran, rivaroxaban or phenprocoumon effectively inhibits platelet activation and thrombin generation at the site of plug formation in healthy subjects. For single doses, rivaroxaban caused a more sustained inhibition of F 1+2 and TAT formation than dabigatran or phenprocoumon at INR Addendum S. Weisshaar drafting the manuscript, statistical analysis and interpretation of data. B. Litschauer statistical analysis and interpretation of data. G. Gouya critical revision of the manuscript for important intellectual content. P. Mayer, L. Smerda and S. Kapiotis acquisition and analysis of data. P. A. Kyrle, S. Eichinger and M. Wolzt study concept and design, interpretation of data and critical revision of the manuscript for important intellectual content. Disclosure of Conflict of Interests Quantification of ticagrelor and AR-C124910XX plasma concentrations was done by Astra Zeneca, Sweden. Measurement of dabigatran concentrations was performed by Boehringer-Ingelheim, Germany. Supporting Information Additional Supporting Information may be found in the online version of this article: Fig. S1. Individual response curves of shed blood b-thromboglobulin (b-tg) within different study cohorts (A = dabigatran, B = rivaroxaban, C = phenprocoumon). Fig. S2. Individual response curves of shed blood prothrombin fragment 1+2 (F 1+2 ) within different study cohorts (A = dabigatran, B = rivaroxaban, C = phenprocoumon). Fig. S3. 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