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ZusammenfassungNach interventionellen Eingriffen an der Aortenklappe oder den atrioventrikulären (AV) Klappen (u. a. TAVI, M-TEER, T-TEER) wird prinzipiell eine antithrombotische Therapie empfohlen. Dabei muss differenziert werden zwischen Patienten, für die unabhängig vom Klappeneingriff eine Indikation zur oralen Antikoagulation (OAC) besteht, meist aufgrund von Vorhofflimmern (AF), und Patienten ohne OAC-Indikation. Mehrere randomisierte Studien konnten zeigen, dass bei AF-Patienten, die eine TAVI erhalten, eine Fortführung der OAC (Vitamin-K-Antagonisten oder NOAC) als Monotherapie einer dualen Therapie, bestehend aus OAC plus zusätzliche Thrombozyteninhibition, überlegen ist. Andererseits ist bei TAVI-Patienten ohne vorbestehende OAC-Indikation eine ASS-Monotherapie als postinterventionelle antithrombotische Therapie zu empfehlen. Nach segelbasierter (Edge-to-Edge) Rekonstruktion der Mitral- und Trikuspidalklappe wird bei bestehender OAC-Indikation eine Fortsetzung der Antikoagulation empfohlen, ansonsten ASS dauerhaft mit Clopidogrel für 1–3 Monate. Die optimale antithrombotische Therapie im Kontext interventioneller Eingriffe an den AV-Klappen ist jedoch bislang nicht in größeren randomisierten Studien untersucht.

Atherothrombosis is a frequent cause of cardiovascular mortality. It is mostly triggered by plaque rupture and exposure of the thrombogenic subendothelial matrix, which initiates platelet aggregation and clot formation. Current antithrombotic strategies, however, target both thrombosis and physiological hemostasis and thereby increase bleeding risk. Thus, there is an unmet clinical need for optimized therapies. Neutrophil activation and consecutive interactions of neutrophils and platelets contribute mechanistically to thromboinflammation and arterial thrombosis, and thus present a potential therapeutic target. Platelet–neutrophil interactions are mediated through adhesion molecules such as P-selectin and P-selectin glycoprotein ligand 1 as well as glycoprotein Ib and macrophage-1 antigen, which mediate physical cell interactions and intracellular signaling. Release of soluble mediators as well as direct signaling between platelets and neutrophils lead to their reciprocal activation and neutrophil release of extracellular traps, scaffolds of condensed chromatin that play a prothrombotic role in atherothrombosis. In this article, we review the role of neutrophils and neutrophil-derived prothrombotic molecules in platelet activation and atherothrombosis, and highlight potential therapeutic targets.

Despite dual antiplatelet therapy patients undergoing percutaneous coronary intervention (PCI) continue to experience periprocedural ischemic events. In addition, all currently used antithrombotic drugs increase the bleeding risk. Thus, there is an unmet clinical need for antithrombotic strategies with improved efficacy and no increase in bleeding. Revacept is a novel, lesion-directed antithrombotic drug that does not interfere with the function of circulating platelets. This dimeric fusion protein of the extracellular domain of glycoprotein VI (the major platelet collagen receptor) and the human Fc-fragment inhibits collagen-mediated platelet adhesion and subsequent aggregation at the site of vascular injury. The randomized, double-blinded, phase II ISAR-PLASTER trial is based on extensive preclinical evaluation of Revacept and a favorable first-in-man trial. A total of 332 patients with stable coronary artery disease undergoing elective PCI will be randomized to either Revacept 160 mg, Revacept 80 mg, or placebo administered as single intravenous infusion directly before the intervention, on top of standard dual antiplatelet therapy and either heparin or bivalirudin, based on local practice and current guidelines. The primary endpoint is the composite of death or myocardial injury (defined as increase in high sensitivity troponin T ≥ 5 times the upper limit of normal) at 48 hours. The safety endpoint is bleeding of class 2 or higher according to the Bleeding Academic Research Consortium at 30 days. This phase II randomized, double blind trial will assess for the first time the efficacy and safety of Revacept—a lesion-directed inhibitor of platelet adhesion—in patients undergoing elective PCI.

Beyond thromboembolic events, peri-procedural bleeding remains one of the most frequent complications after transcatheter aortic valve implantation (TAVI). The majority of TAVI patients receive a dual anti-platelet treatment (DAPT) regimen. This analysis from the EVERY-TAVI register database aimed to analyse whether the level of on-treatment adenosine diphosphate-induced platelet reactivity predicts early outcomes at 30 days after TAVI. A total of 146 consecutive TAVI patients on DAPT who underwent platelet function testing with the Multiplate analyser were included here. Definition of bleeding events was done according to the Valve Academic Research Consortium-2 (VARC-2) classification. In our cohort, a status of low platelet reactivity (LPR, ≤ 18 units) was observed in 79 patients (54%), while high platelet reactivity (HPR, ≥ 46 units) was present in 18 patients (12%). At 30-day follow-up, the incidence of VARC-2 bleeds was 45.6% (n = 36) in LPR patients and 23.9% (n = 16) in patients without LPR (hazard ratio [HR] 2.10, 95% confidence interval [CI], 1.17–3.79; p = 0.01). In age-adjusted multivariate analysis, a status of LPR was independently associated with VARC-2 bleeding events (HRadj, 2.06, 95% CI, 1.14–3.71; p = 0.02). HPR was not associated with the 30-day risk of death, stroke, or myocardial infarction (p ≥ 0.43). In summary, presence of LPR was associated with bleeding events in patients undergoing TAVI while presence of HPR was not associated with ischaemic outcomes at 30 days. The value of platelet function testing for bleeding risk prediction and for a possible guidance of anti-thrombotic treatment in the elderly TAVI population warrants further investigation.

Was ist neu? Risikostratifizierung der Dualen Plättcheninhibition (DAPT) Die neuen Leitlinien befassen sich mit grundlegenden Empfehlungen zu Form und Dauer der DAPT. Die Individualisierung der Therapie liegt deutlich im Fokus. Dabei wird geraten, mithilfe von Expertenteams bzw. Scores das individuelle Ischämie- bzw. Blutungsrisiko des jeweiligen Patienten einzuschätzen. In Abhängigkeit davon wird die Dauer einer DAPT festgelegt. Dabei wird hervorgehoben, dass die Entscheidung über die DAPT-Dauer dynamisch ist und in regelmäßigen Abständen reevaluiert werden sollte. Duale Plättchenhemmung nach elektiver koronarer Stentimplantation Aufgrund der durch die neuen Stenttechnologien deutlich seltener auftretenden Stentthrombosen ist erstmals die Dauer der DAPT unabhängig vom Stenttyp (Bare-metal- oder Drug-eluting-Stent). Dabei ist eine Dauer von einem Monat bis zu 36 Monaten möglich. Damit hat sich die Sicht der DAPT von einer stentbezogenen auf eine systemische Behandlungsstrategie gewandelt. Duale Plättchenhemmung im Rahmen eines akuten Koronarsyndroms In diesem Kontext wurden auch die Empfehlungen zur DAPT angepasst bei Patienten mit akutem Koronarsyndrom (ACS), die konservativ behandelt werden (inklusive Patienten mit Myokardinfarkt bei nicht okkludierten Koronararterien) und bei denjenigen, die mit einer Bypassoperation versorgt werden. In beiden Gruppen wird eine konsequente DAPT empfohlen. Deren Dauer richtet sich ebenfalls nach dem individuellen Blutungsrisiko des jeweiligen Patienten. Hinsichtlich des Starts einer DAPT bei Patienten mit Nicht-ST-Strecken-Hebungsinfarkt wird nun geraten, das Loading mit einem P2Y12-Hemmer (Ticagrelor oder Clopidogrel) bereits bei Diagnose durchzuführen, sofern eine Koronarangiografie angedacht ist. Duale Plättchenhemmung bei Patienten mit Indikation zur dauerhaften Antikoagulation Ebenfalls gibt es Neuerungen der Empfehlungen zu Patienten mit Koronarintervention und zusätzlicher Indikation einer dauerhaften effektiven Antikoagulation bei Vorhofflimmern. Die Guidelines positionieren sich dahingehend, dass die Vorteile von oralen Nicht-Vitamin-K-Antikoagulanzien (NOAK) gegenüber Marcumar auch bei diesen Patienten Bestand haben könnten. Daher sei ein NOAK anstatt von Marcumar in Erwägung zu ziehen. Auch wird empfohlen, die Dauer der DAPT in Kombination mit oraler Antikoagulation (Triple-Therapie) in Abhängigkeit vom individuellen Ischämie- und Blutungsrisiko zu wählen. Dabei wird nun auch die Möglichkeit eingeräumt, eine Triple-Therapie lediglich periinterventionell anzuwenden und bereits bei Krankenhausentlassung auf ein duales Regime mit oraler Antikoagulation und einem Thrombozytenfunktionshemmer (Aspirin oder Clopidogrel) zu wechseln.

SummaryOutcomes of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) have been significantly improved with the use of potent P2Y12 receptor inhibitors like prasugrel. While most of the ischaemic risk reduction for prasugrel versus clopidogrel was demonstrated in the early treatment period, the risk of bleeding became particularly prominent during the chronic course of therapy. It may therefore be a valid approach to substitute prasugrel for clopidogrel in the early phase of chronic antiplatelet treatment after PCI. In the Testing Responsiveness To Platelet Inhibition On Chronic Antiplatelet Treatment For Acute Coronary Syndromes (TROPICAL-ACS) trial, we aim to compare standard prasugrel therapy with a de-escalating antiplatelet treatment approach guided by platelet function testing (PFT). The study is an investigator-initiated European multicentre, randomised clinical trial in biomarker-positive ACS patients after successful PCI. Two thousand six hundred patients will be randomised prior to hospital discharge in a 1:1 fashion to either receive standard prasugrel therapy (control group) or de-escalating therapy (one-week prasugrel followed by one-week clopidogrel and PFT-guided maintenance therapy from day 14 after hospital discharge, monitoring group). Patients of the monitoring group with high on-clopidogrel platelet reactivity (HPR) based on Multiplate analyzer testing (HPR: ≥ 46U per consensus definition) will be switched back to prasugrel, whereas those without HPR (ClinicalTrials.gov Identifier: NCT01959451

SummaryPlatelets actively participate in inflammatory processes and drive diseases such as atherosclerosis, rheumatoid arthritis and cancer metastasis. However, platelets also have anti-inflammatory and anti-infective properties, which have received less consideration in the past. In this review, we highlight recent findings on the role of platelets in host defense and describe regulatory pathways modulating immuneresponses. Furthermore, we discuss the role of platelets for the resolution of inflammation and tissue repair. These conceptual changes contribute to our understanding of platelet biology in disease.

SummaryThere is limited clinical data comparing different P2Y12-receptor inhibitors in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock. The aim of the ISAR-SHOCK registry was to compare the clinical outcome of patients treated with clopidogrel vs prasugrel in this setting. Patients (n=145) with AMI complicated by cardiogenic shock and undergoing primary PCI in two centres (Deutsches Herzzentrum München and Klinikum rechts der Isar, Technical University Munich) between January 2009 and May 2012 were included in this registry. The use of prasugrel for patients within this registry reflected co-morbidities and platelet function testing results during the acute AMI phase. Early outcome at 30-days was reported with regard to all-cause mortality, myocardial infarction (MI), stent thrombosis (ST) and bleeding events. With regard to antiplatelet treatment in the 145 cardiogenic shock patients, 50 patients were initially treated or immediately switched to prasugrel while 95 patients were treated with clopidogrel. All-cause mortality was lower in prasugrelvs clopidogrel-treated patients (30 % vs 50.5%, HR: 0.51, 95% CI [0.29–0.92], p=0.025). No significant differences in prasugrel- vs clopidogrel-treated patients were observed for the occurrence of MI (p=0.233), ST (p=0.306) or TIMI major bleedings (p=0.571). Results of the ISAR-SHOCK registry suggest that the use of prasugrel in AMI patients complicated by cardiogenic shock might be associated with a lower mortality risk as compared to clopidogrel therapy without increasing the risk of bleeding. These findings, however, need confirmation from specifically designed randomised studies in this high-risk cohort of patients.

SummaryBlood platelets are highly activated in the setting of an acute coronary syndrome (ACS). This fact mandates the need for potent platelet inhibition in ACS patients and especially in patients undergoing a percutaneous coronary intervention (PCI). The 2nd generation thienopyridine clopidogrel has been the standard of treatment in the past. Due to its pharmacological properties including a delayed onset of action, a large response variability and an insufficient antiplatelet action in some patients (low responsiveness or high on-treatment platelet reactivity), there was a need to develop, to study and to introduce more potent agents with a fast, reliable and potent antiplatelet action. With the 3rd generation thienopyridine prasugrel and with ticagrelor two potent agents for antiplatelet treatment of ACS patients are available now. Both drugs have demonstrated their superiority compared to clopidogrel in terms of thrombotic risk reduction in large-scale randomized trials. However, for these agents and in line with the expectations towards a more potent anti platelet treatment regimen, a higher risk for bleeding was observed for prasugrel and ticagrelor. Further on, the new anti platelet agents have their own and characteristic contraindications and numerous issues to be considered in clinical practice.This review aims to provide an overview on the state of the art P2Y12 receptor directed inhibition in ACS patients with a focus on patients undergoing a coronary stenting procedure.

SummaryGlycoprotein VI (GPVI) is the major platelet collagen receptor and plays a critical role in the process of thrombosis at sites of atherosclerotic lesions. This study evaluates the feasibility of radiolabeled soluble GPVI to identify injured arterial lesions. Radiolabeling was carried out using the iodogen method and resulted in the radioiodinated GPVI in radiochemical yields between 97–100%. The biodistribution of [125I]GPVI was determined in normal mice and demonstrated a blood clearance halftime of approximately 5.5 hours. Vascular lesions were induced in the carotid artery in wild type and ApoE -/- mice. Immediately after injury radioiodinated GPVI was injected intravenously. Binding of [123I]GPVI to carotid lesions was assessed by szinti-graphic in vivo imaging. Carotid arteries were explanted for ex vivo autoradiography and histological characterization of the lesion. In vivo and ex vivo imaging revealed substantial accumulation of radioiodinated GPVI in the injured artery wall, with a ratio of lesion to control vessel of 3:1 and 7:1, respectively. Because GPVI is the critical collagen receptor that mediates platelet adhesion to vascular lesions, soluble radiolabeled GPVI may be an agent for non-invasive imaging of thrombogenic thus, vulnerable atherosclerotic plaques.

Coronary atherosclerosis is the primary cause of heart diseases in industrialized nations. It has now become clear that coronary atherosclerosis is not simply an inevitable consequence of aging but rather a chronic inflammatory process that can be converted into an acute clinical event by plaque rupture and arterial thrombosis. It is well recognized that platelets play a key role in thrombotic vascular occlusion at the ruptured coronary atherosclerotic plaque, leading to acute ischemic episodes, the acute coronary syndromes (ACSs). In addition, both embolization of platelet aggregates and direct, receptor-mediated platelet adhesion to the postischemic microvascular surface result in obstruction and impairment of coronary microcirculation. Such microvascular disturbance may lead to significant additional tissue injury and aggravate myocardial contractile dysfunction. Novel antiplatelet strategies have contributed substantially to improve the outcome of patients with ACSs. However, the availability of new investigative tools, including genetically modified mouse models of disease, has demonstrated that platelets not only contribute to acute thrombotic vascular occlusion but also participate in the inflammatory and matrix-degrading processes of coronary atherosclerosis itself. Platelet- endothelial cell interactions at lesion-prone sites might trigger an inflammatory response in the vessel wall early in the genesis of atherosclerosis and contribute to destabilization of advanced atherosclerotic lesions. Thus, recent progress in defining the complex multistep process that promotes firm arrest of platelets to the (sub-) endothelium and initiates subsequent platelet activation may lead to the development of new antiplatelet strategies that provide an efficacious prophylactic intervention, in particular, for patients with a high atherosclerotic risk factor profile.

There’s life in the old dog yet: Clopidogrel competing with prasugrel and ticagrelor for treatment of ACS patients