Universitäts-Herzzentrum Freiburg • Bad Krozingen

DRKS00033035.

Prognosis and haemostasis of dialysis patients with concomitant Atrial Fibrillation (AF) or Coronary Artery Disease (CAD)

Dialysis patients with concomitant AF or CAD are at higher risks of both bleeding and thrombosis.  These patients are often excluded in the drug trials, due to their multimorbidity and the different pharmacokinetics - pharmacodynamics. As a consequence, patients undergoing dialysis are mostly treated with off-label therapy without enough data about the efficacy and safety.

In this study, we will investigate the clinical outcomes and coagulation parameters of dialysis patients with concomitant AF or CAD, which will be compared to patients with stage 4 chronic renal insufficiency. We will focus on AF or CAD separately. In the AF study, the primary outcome is defined as time to the composite of all-cause death and bleeding at 6 months, assessed by telephone. The secondary outcomes include time to myocardial infarction or stroke at 6 months and the coagulation parameters (AXA, PPT, INR) measured at baseline. In the CAD study, the primary outcome is defined as time to the composite of MACE (all-cause death, myocardial infarction, stroke) assessed at 6 months. The secondary outcomes include time to bleeding at 6 months and platelet function testing with Multiplate Analyzer at baseline.

The analysis of both, clinical outcomes and biomarkers will help to better understand the hemostasis of patients on dialysis and personalize the antithrombotic therapy.

This project is funded by Else Kröner-Fresenius Stiftung

Aortic valve stenosis (AVS) is the most common primary valve disease in high-income countries and AVS is associated with high mortality. Especially in eldery patients with an increased surgical risk, transcatheter aortic valve replacement (TAVR) offers several advantages compared to surgical aortic valve replacement, the current standard of care. Nevertheless, there is a high risk of atherothrombotic complications such as stroke in the first months after TAVR. Guidelines recommend dual antiplatelet therapy (DAPT) after TAVR with optional duration between 3 to 6 months. The optimal choice of antithrombotic therapy according to individual thrombotic and bleeding risk is not known.
Aim: With this singe center prospective observational cohort study, we aim to establish a hemostatic profile for patients after TAVR. The aim is to evaluate new biomarkers by various analyzes of blood samples (i.e., thromboelastography [TEG], multiple electrode aggregometry, ClotPro®). Furthermore, CYP2C19 status, soluble hemostatic (bio)markers (i.e., P-selectin, GPVI, NET parameters DNA and H3cit, pro-inflammatory cytokines, miRNAs assessed by Real time quantitative polymerase chain reaction (RTqPCR), Enzyme-linked Immunosorbent Assay (ELISA) and cell-based hemostatic (bio)markers: neutrophil CD11b, platelet serotonylation, PAR-1, reticulated platelets, platelet-neutrophil aggregation, platelet monocyte aggregation, activated GPIIb/IIIa, platelet transcriptome assessed by Fluorescence-activated cell sorting (FACS), Enzyme -linked Immunosorbent Assay (ELISA) and Real time quantitative Polymerase chain reaction (RTqPCR) will be assessed. These markers will be used to identify patients with an increased risk for thrombotic or bleeding events to enable a personalized antithrombotic therapy.

Venous thromboembolism is one of the most common cardiovascular diseases with a high mortality. In most of the cases, a reperfusion represents the only causal therapy. Current guidelines indicate a reperfusion therapy for high-risk patients. However, for intermediate to high-risk patients there is no therapy recommendation, the decision should be made by the clinical physician. Lyse present the standard of care therapy for reperfusion which could be accompanied with bleeding complications. Since 2018 on University Heart center of Freiburg EKOS^TM endovascular system (Boston, scientific), an interventional device, using ultrasound-assisted catheter-directed thrombolysis for treatment of pulmonary embolism was used. This is a local infusion therapy requiring less lytic agents which causes less bleeding side effects. Aim of this study is to evaluate EKOS^TM system therapy in patients with pulmonary embolism in a retrospective single center study on University Heart Center in Freiburg.  All patients of the last 4 years with EKOS-therapy in the department of cardiology and angiology will be included in this study and technical (successful catheter installation) and clinical outcome (e.g., survival, bleeding, chronic-thromboembolic pulmonal hypertension, resilience, and re-embolism) will be evaluated.

RISTRATAVI
Transcatheter aortic valve implantation (TAVI) has become the standard of care in elderly patients at increased risk for surgical aortic valve replacement. However, the optimal antithrombotic strategy post TAVI is still unclear. Current European guidelines recommend dual antiplatelet therapy (DAPT) for 3 to 6 months.The prevalence of subclinical leaflet thrombosis after TAVI is 15% up to 40%, but its clinical long-term relevance is uncertain. Thromboelastography (TEG(R)) can be used as a point-of-care system evaluating a patient's individual hemostasis profile. For the detection of transcatheter valve thrombosis it may be superior to conventional platelet function testing because global hemostasis can be assessed in addition to platelet function. We intend an observational trial recruiting patients undergoing TAVI under standard care. At defined time points serially TEG(R) as well as further platelet function testing (multiple electrode aggregometry) and conventional coagulation testing were performed. The primary objective is to find surrogate TEG-derived markers/ models predicting the development of a subclinical leaflet thrombosis after TAVI under usual care. The secondary objective is to find TEG-derived markers / models identifying patients at an increased risk after TAVI (all-cause mortality, cardiovascular mortality, thromboembolic and bleeding events).

Clopidogrel is the most prescribed P2Y12-receptor antagonist after PCI in AF patients and has shown significant interpatient variability of on-treatment platelet reactivity. High on-clopidogrel treatment platelet reactivity is associated with an increased risk for ischemic events particularly stent thrombosis. In context of HPR-AF-PCI pilot study and HPR-TEG-AF-PCI we investigated the association of CYP2C19 genotype with antiplatelet effect of clopidogrel and ischemic and bleeding risk in patients with AF undergoing PCI.  Patients with AF after PCI were grouped according to CYP2C19*2 and *17 diplotypes: *2/non-17* or *2/*2 as reduced metabolizers (RM), non-*2/*17 or *17/*17 as increased metabolizers (IM), and the remaining as normal metabolizers (NM). Platelet aggregation was quantified by multiple electrode aggregometry (MEA) or thromboelastography (TEG). The primary outcome was assessed at 6 months and was defined as time to death, myocardial infarction, or stroke. The secondary outcome was time to non-major clinically relevant (NMCR) or major bleeding according to the ISTH classification.

DRKS00021212
DRKS00024509

These two prospective single center observational cohort studies focus on antithrombotic therapy in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI).

Approximately one-third of patients with AF have coexisting coronary artery disease (CAD), in many cases requiring PCI or leading to acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) is the preferred antithrombotic strategy after PCI or ACS but is not typically adequate to protect most patients with AF from thromboembolic events caused by AF. Clopidogrel is the most prescribed P2Y12-receptor antagonist after PCI and has shown significant interpatient variability of on-treatment platelet reactivity. High on-clopidogrel treatment platelet reactivity is associated with an increased risk for ischemic events particularly stent thrombosis. Platelet function testing during P2Y12-inhibitor therapy identifies PCI-treated patients at higher risk for mortality and stent thrombosis or at an elevated risk for bleeding. The aim of these two studies were to assess the association of high on-clopidogrel platelet reactivity with ischemic events (i.e., myocardial infarction, stroke, or all cause death) in patients with atrial fibrillation undergoing a percutaneous coronary intervention with stent Implantation who are treated with oral anticoagulation and Clopidogrel. Platelet function will be assessed in patients with AF (atrial fibrillation) following one or three) days after stent implantation with multiple electrode (-impendance) aggregometry (HPR-AF-PCI study) or thromboelastography (HPR-TEG-AF-PCI), respectively. Primary ischemic outcome was definded as time to composite of all-cause death, myocardial infarction, or stroke (MACE) at 6 months, assessed by telephone. Secondary outcome was defined as time to Major or clinically relevant non-major bleeding as defined by the International Society of Thrombosis and Haemostasis (ISTH)

• Olivier CB, Middleton SK, Purington N, Shashidhar S, Hereford J, Mahaffey KW, Turakhia MP. Why digital health trials can fail: Lessons learned from a randomized trial of health coaching and virtual cardiac rehabilitation. Cardiovasc Digit Health J. 2021 Feb 9;2(2):101-108. doi: 10.1016/j.cvdhj.2021.01.003. PMID: 35265897; PMCID: PMC8890340.
• Heger LA, Glück T, Kaier K, Hortmann M, Rieder M, Siegel PM, Diehl P, Wengenmayer T, Olivier CB, Bode C, Busch HJ, Duerschmied D, Ahrens I. Medical history of coronary artery disease and time to electrocardiogram in the emergency department: a real-life, single-center, retrospective analysis. BMC Cardiovasc Disord. 2021 Oct 7;21(1):480. doi: 10.1186/s12872-021-02274-1. PMID: 34620090; PMCID: PMC8496093.
• Siegel PM, Sander L, Fricke A, Stamm J, Wang X, Sharma P, Bassler N, Ying YL, Olivier CB, Eisenhardt SU, Bode C, Ahrens I, Diehl P, Peter K. P2Y12 receptor blockers are anti-inflammatory drugs inhibiting both circulating monocytes and macrophages including THP-1 cells. Sci Rep. 2021 Aug 31;11(1):17459. doi: 10.1038/s41598-021-95710-3. PMID: 34465804; PMCID: PMC8408182.
• Piepenburg SM, Kaier K, Olivier CB, Bothe W, Heidt T, Jäckel M, Peikert A, Wolf D, Zehender M, Bode C, Dürschmied D, von Zur Mühlen C, Stachon P. Use and Outcomes of Acute Treatment Strategies in Patients with Severe Aortic Valve Stenosis. Glob Heart. 2021 Dec 27;16(1):91. doi: 10.5334/gh.1055. PMID: 35141132; PMCID: PMC8719472.
• Jank M, von Niessen N, Olivier CB, Schmitt H, Anto-Michel N, Hilgendorf I, Bode C, Moser M, Esser JS, Zhou Q. Platelet Bone Morphogenetic Protein-4 Mediates Vascular Inflammation and Neointima Formation after Arterial Injury. Cells. 2021 Aug 8;10(8):2027. doi: 10.3390/cells10082027. PMID: 34440796; PMCID: PMC8394465.

• Heger LA, Danzer M, Bode C, Hortmann M, Duerschmied D, Olivier CB, Moser M. Dual-Pathway Antithrombotic Therapy in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention in Stable Coronary Artery Disease: A Single-Center, Single-Operator, Retrospective Cohort Study. Front Med (Lausanne). 2020 Sep 30;7:414. doi: 10.3389/fmed.2020.00414. PMID: 33117822; PMCID: PMC7561383.
• Olivier CB, Sundaram V, Chertow GM, Shashidhar S, McDonnell LK, Ding VY, Desai M, Mahaffey KW, Mell M. A double-blind, randomized, placebo-controlled pilot trial to evaluate safety and efficacy of vorapaxar on arteriovenous fistula maturation. J Vasc Access. 2020 Jul;21(4):467-474. doi: 10.1177/1129729819887269. Epub 2019 Nov 27. PMID: 31774037; PMCID: PMC8063544.
• Leef GC, Perino AC, Askari M, Fan J, Ho PM, Olivier CB, Longo L, Mahaffey KW, Turakhia MP. Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration. J Pharm Pract. 2020 Oct;33(5):647-653. doi: 10.1177/0897190019828270. Epub 2019 Feb 21. PMID: 30791808.

• Olivier CB, Mulder H, Hiatt WR, Jones WS, Fowkes FGR, Rockhold FW, Berger JS, Baumgartner I, Held P, Katona BG, Norgren L, Blomster J, Patel MR, Mahaffey KW. Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. JAMA Cardiol. 2019 Jan 1;4(1):7-15. doi: 10.1001/jamacardio.2018.4171. PMID: 30540355; PMCID: PMC6439683.
• Yong CM, Sundaram V, Abnousi F, Olivier CB, Yang J, Stone GW, Steg PG, Michael Gibson C, Hamm CW, Price MJ, Deliargyris EN, Prats J, White HD, Harrington RA, Bhatt DL, Mahaffey KW; CHAMPION PHOENIX Investigators. The efficacy and safety of cangrelor in single vessel vs multivessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX. Clin Cardiol. 2019 Jun 29;42(9):797–805. doi: 10.1002/clc.23221. Epub ahead of print. PMID: 31254472; PMCID: PMC6727881.
• Olivier CB, Fan J, Askari M, Mahaffey KW, Heidenreich PA, Perino AC, Leef GC, Ho PM, Harrington RA, Turakhia MP. Site Variation and Outcomes for Antithrombotic Therapy in Atrial Fibrillation Patients After Percutaneous Coronary Intervention. Circ Cardiovasc Interv. 2019 Aug;12(8):e007604. doi: 10.1161/CIRCINTERVENTIONS.118.007604. Epub 2019 Aug 16. PMID: 31416357.
• Olivier CB, Bhatt DL, Leonardi S, Stone GW, Gibson CM, Steg PG, Hamm CW, Wilson MD, Mangum S, Price MJ, Prats J, White HD, Lopes RD, Harrington RA, Mahaffey KW; CHAMPION PHOENIX Investigators *. Central Adjudication Identified Additional and Prognostically Important Myocardial Infarctions in Patients Undergoing Percutaneous Coronary Intervention. Circ Cardiovasc Interv. 2019 Jul;12(7):e007342. doi: 10.1161/CIRCINTERVENTIONS.118.007342. Epub 2019 Jul 12. PMID: 31296081.
• Olivier CB, Sundaram V, Chertow GM, Shashidhar S, McDonnell LK, Ding VY, Desai M, Mahaffey KW, Mell M. A double-blind, randomized, placebo-controlled pilot trial to evaluate safety and efficacy of vorapaxar on arteriovenous fistula maturation. J Vasc Access. 2020 Jul;21(4):467-474. doi: 10.1177/1129729819887269. Epub 2019 Nov 27. PMID: 31774037; PMCID: PMC8063544.
• Leef GC, Perino AC, Askari M, Fan J, Ho PM, Olivier CB, Longo L, Mahaffey KW, Turakhia MP. Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration. J Pharm Pract. 2020 Oct;33(5):647-653. doi: 10.1177/0897190019828270. Epub 2019 Feb 21. PMID: 30791808.
• Bode C, Olivier CB, Duerschmied D. Anticoagulation and anaemia: old opponents from the era of VKA? Eur Heart J. 2019 Dec 7;40(46):3791-3792. doi: 10.1093/eurheartj/ehz628. PMID: 31504440.
• Bode C, Olivier CB, Duerschmied D. Is Bleeding Always Bad?: Bad Boy Bleeding. J Am Coll Cardiol. 2019 Sep 24;74(12):1529-1531. doi: 10.1016/j.jacc.2019.07.066. PMID: 31537260.

• Rilinger J, Heilmann C, Beitinger U, Olivier CB, Diehl P, Beyersdorf F, Siepe M. Moderate ischemic mitral regurgitation: coronary artery bypass grafting with versus without simultaneous treatment of the mitral valve. J Cardiovasc Surg (Torino). 2018 Dec;59(6):830-835. doi: 10.23736/S0021-9509.18.10413-7. Epub 2018 Mar 12. PMID: 29532654.
• Olivier CB, Sundaram V, Bhatt DL, Leonardi S, Lopes RD, Ding VY, Yang L, Stone GW, Steg PG, Gibson CM, Hamm CW, Price MJ, White HD, Desai M, Lynch DR Jr, Harrington RA, Mahaffey KW; CHAMPION PLATFORM and CHAMPION PCI Investigators. Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials. Int J Cardiol. 2018 Nov 1;270:96-101. doi: 10.1016/j.ijcard.2018.06.034. Epub 2018 Jun 8. PMID: 29937301; PMCID: PMC8117171.
• Olivier CB, Turakhia MP, Mahaffey KW. Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome. Expert Opin Drug Saf. 2018 Mar;17(3):251-258. doi: 10.1080/14740338.2018.1424827. Epub 2018 Jan 24. PMID: 29363352.

• Olivier CB, Weik P, Meyer M, Weber S, Diehl P, Bode C, Moser M, Zhou Q. Dabigatran and rivaroxaban do not affect AA- and ADP-induced platelet aggregation in patients receiving concomitant platelet inhibitors. J Thromb Thrombolysis. 2016 Aug;42(2):161-6. doi: 10.1007/s11239-016-1350-7. PMID: 26961375.
• Olivier CB, Schnabel K, Weber S, Zhou Q, Bode C, Moser M, Diehl P. Platelet reactivity after administration of third generation P2Y12-antagonists does not depend on body weight in contrast to clopidogrel. J Thromb Thrombolysis. 2016 Jul;42(1):84-9. doi: 10.1007/s11239-016-1340-9. PMID: 26837379.
• Olivier CB, Meyer M, Bauer H, Schnabel K, Weik P, Zhou Q, Bode C, Moser M, Diehl P. The Ratio of ADP- to TRAP-Induced Platelet Aggregation Quantifies P2Y12-Dependent Platelet Inhibition Independently of the Platelet Count. PLoS One. 2016 Feb 17;11(2):e0149053. doi: 10.1371/journal.pone.0149053. PMID: 26885820; PMCID: PMC4757031.
• Rilinger J, Meyer M, Schnabel K, Weik P, Charlet A, Esser JS, Zhou Q, Bode C, Moser M, Diehl P, Olivier CB. High platelet reactivity after P2Y12-inhibition in patients with atrial fibrillation and coronary stenting. J Thromb Thrombolysis. 2016 Nov;42(4):558-65. doi: 10.1007/s11239-016-1397-5. PMID: 27387715.
• Zhou Q, Einert M, Schmitt H, Wang Z, Pankratz F, Olivier CB, Bode C, Liao JK, Moser M. MnTBAP increases BMPR-II expression in endothelial cells and attenuates vascular inflammation. Vascul Pharmacol. 2016 Sep;84:67-73. doi: 10.1016/j.vph.2016.07.001. Epub 2016 Jul 8. PMID: 27401963; PMCID: PMC5563469.

• Olivier CB, Weik P, Meyer M, Weber S, Anto-Michel N, Diehl P, Zhou Q, Geisen U, Bode C, Moser M. TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran. Thromb Res. 2016 Feb;138:63-68. doi: 10.1016/j.thromres.2015.10.038. Epub 2015 Nov 1. PMID: 26610745.

• Olivier CB, Schnabel K, Brandt C, Weik P, Olschewski M, Zhou Q, Bode C, Diehl P, Moser M. A high ratio of ADP-TRAP induced platelet aggregation is associated more strongly with increased mortality after coronary stent implantation than high conventional ADP induced aggregation alone. Clin Res Cardiol. 2014 Dec;103(12):968-75. doi: 10.1007/s00392-014-0737-8. Epub 2014 Jul 16. PMID: 25027180.
• Olivier CB, Diehl P, Schnabel K, Weik P, Zhou Q, Bode C, Moser M. Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry. Thromb Haemost. 2014 Feb;111(2):266-72. doi: 10.1160/TH13-06-0508. Epub 2013 Oct 31. PMID: 24172891.
• Olivier CB, Weik P, Meyer M, Weber S, Anto-Michel N, Diehl P, Zhou Q, Geisen U, Bode C, Moser M. TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran. Thromb Res. 2016 Feb;138:63-68. doi: 10.1016/j.thromres.2015.10.038. Epub 2015 Nov 1. PMID: 26610745.
• Olivier CB, Diehl P, Bode C, Moser M. Antithrombozytäre Therapie nach akutem Koronarsyndrom. Differenzialtherapie und Dauer [Antiplatelet therapy after acute coronary syndrome. Therapeutic strategies and treatment duration]. Herz. 2014 Nov;39(7):808-13. German. doi: 10.1007/s00059-014-4162-6. PMID: 25359405.
• Moser M, Olivier CB, Bode C. Triple antithrombotic therapy in cardiac patients: more questions than answers. Eur Heart J. 2014 Jan;35(4):216-23. doi: 10.1093/eurheartj/eht461. Epub 2013 Dec 2. PMID: 24302275.