Solid cancers after antiplatelet therapy: Confirmations, controversies, and challenges

© Schattauer 2015. The role of anticoagulants and antiplatelet agents in tumour growth and prognosis is not new, and currently under intense investigation. Some randomised data strongly suggest that this association exists, but it is complex, and not necessarily pointed at the same direction. The potential mechanisms responsible for such harmful association include a direct hazard of novel antithrombotics on cancer, indirect promotion of tumour growth, easier metastatic dissemination due to instability of platelet-tumour cell aggregates, or/and inability to keep cancer cells locally in situ are considered. The latest randomised evidence ultimately rejected the drug-specific cancer risks, clearly indicating the class-effect. In lay terms “cancers follow bleeding”, which seems to be true for antithrombotic agents in general. Significant excess of solid cancers which was similar after prasugrel in TRITON, and with vorapaxar in TRACER trials was confirmed by the FDA reviews. Later, extra cancer deaths reported following clopidogrel and prasugrel in DAPT, and after ticagrelor in PEGASUS are also of concern. However, there are remaining controversies with regard to published cancer risks after ticagrelor (PLATO), or another vorapaxar trial (TRA2P), while full disclosure of separate clopidogrel and prasugrel cancer data in DAPT is still lacking. In short, if we apply moderate antiplatelet strategies for over two years, or aggressive regimens including triple therapy for much less than one year, the solid cancer risks emerge. Currently, more delicate platelet inhibition, and shorter exposure to dual oral antiplatelet agents should prevail

Mortality and cancer after 12 versus 30 months dual antiplatelet therapy: The Korean outcomes registry evaluating antithrombotics (Korea)

© Schattauer 2017.The optimal duration and cancer risks of antiplatelet therapy following percutaneous coronary intervention (PCI) are unclear. We compared cancer and all-cause mortality after dual antiplatelet therapy (DAPT) for the combination of clopidogrel and aspirin (ASA) versus ASA alone over 18 months follow-up in event-free patients at 12 months DAPT from the Health Insurance Review and Assessment (HIRA) dataset via the Korean Outcomes Registry Evaluating Antithrombotics (KOREA). We selected PCI patients who were event free for 12 months and maintained a consistent antiplatelet regimen for 18 more months. The primary endpoints were any cancer and all-cause mortality at 30 months follow-up after PCI. From 320,351 screened post-PCI patient HIRA records, we excluded 294,413 and qualified 25,938, constituting DAPT (n=10,992) and ASA (n=14,946) groups. The Propensity Score Matching (PSM), and Inverse Probability of Treatment Weighting (IPTW) revealed no significant differences in background demographics and clinical characteristics for DAPT versus ASA patients. At 30-months post-PCI, after massive (>91 %) exclusions, cancer risk was higher for continuous DAPT [455 (4.15 %) vs 606 (4.04 %); HR=1.221; 95 %CI: 1.061-1.405; p=0.005], which remained significant by PSM (p=0.006) or IPTW (p=0.007), while all-cause mortality was similar [136 (1.24 %) vs 192 (1.28 %) HR=0.999; 95 %CI: 0.736-1.135; p=0.993]. This analysis suggests a potential mild excess cancer risk, but no mortality benefit in Korean post-PCI patients treated with DAPT for an additional 18 months beyond conventional 12 months DAPT. These data are not supporting continuing DAPT for more than one year in East Asians. Analysing cancer types and assessing potential cancer association with bleeding are warranted

Reception of Chinese Magic Religious Culture in Ancient Japan -Centering upon belief in Doku-

The present paper mainly examines the reception of belief in Doku in ancient Japan. Doku is a deity of earth taboo, which first appeared at The East Han Dynasty. First it introduces the shared religious phonemes of belief in Doku in east asia. Then it examines the process how belief in Doku recepted in Japan from the following three sections: antakushinjyukyō, which was read early in koutoku reign, has a close relation with Doku; investigating the Chinese books which recorded Doku; discussing who imported the belief in Doku. We can found the reception of belief in Doku closely influenced by the Japanese historic movement, and it was mainly recepted as a deity of magic religion

Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor

A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure–activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile

Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study

<p>Abstract</p> <p>Background</p> <p>Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment.</p> <p>Methods</p> <p>With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B₂(TXB₂)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis.</p> <p>Results</p> <p>The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5'-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r²= 0.49). In opposite, TXB₂-levels decreased with ASA compared to clopidogrel. Serum TXB₂and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone.</p> <p>Conclusion</p> <p>The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB₂for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.</p

Effects of Aspirin on Endothelial Function and Hypertension

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. SUMMARY: Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations