prasugrel-hydrochloride and Colonic-Neoplasms

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.

Topics: Adenosine; Animals; Anticarcinogenic Agents; Aspirin; Blood Platelets; Carcinogenicity Tests; Clopidogrel; Colonic Neoplasms; Drug Therapy, Combination; Female; Humans; Lactones; Male; Mice; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Randomized Controlled Trials as Topic; Rivaroxaban; Sex Factors; Species Specificity; Ticagrelor; Ticlopidine; Time Factors

The TRITON-TIMI 38 was a head-to-head trial to assess the efficacy and safety of the experimental antiplatelet agent prasugrel vs. standard care with clopidogrel on top of aspirin. Besides some ischemic protection at expense of overwhelming bleeding disadvantage, prasugrel treated patients experienced three times higher rate of colonic neoplasms then after clopidogrel, and this difference was significant. Importantly, known gastrointestinal bleeding preceded the diagnosis of colonic neoplasms only in half of the patients. Three potential mechanisms responsible for such harmful association are reviewed, namely: (i) direct hazard of the experimental drug on cancer occurrence and progression; (ii) indirect modulation of tumor growth; and (iii) enhanced metastatic dissemination due to instability of platelet-tumor cell aggregates, or/and inability to keep the disease locally due by much more potent long-term platelet inhibition should be considered. Significant excess of cancer after prasugrel is alarming, and can be reasonably explained, with critical clinical implications not only for prasugrel further development, but also for existing and future chronic antiplatelet strategies. If the hypothesis that oral aggressive platelet inhibition cause higher cancer risks will turn out to be true, then intensity of platelet inhibition, and especially duration of chronic antiplatelet therapy should be reconsidered. More delicate platelet inhibition, and shorter exposure to oral antiplatelet agents will prevail.

Topics: Animals; Aspirin; Clopidogrel; Colonic Neoplasms; Gastrointestinal Hemorrhage; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Thiophenes; Ticlopidine

There was an excess of new solid neoplasms (112 vs. 69), and cancer deaths (24 vs. 15) after prasugrel in the TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition). These cancers usually occur after 4 months following prasugrel, and women are especially at risk. The hypothesis has been offered that prasugrel, but not aspirin or clopidogrel, causes indirect modulation of tumor growth, and/or enhanced metastatic dissemination due to instability of platelet-tumor cell aggregates via the inability to keep cancer locally within the platelet thrombi due to excessive chronic platelet inhibition.. A 70-year old female diabetic patient underwent drug-eluting stent implantation. The patient received a loading dose of prasugrel (60 mg), followed by prasugrel 10 mg/daily as well as aspirin (81 mg/daily). After 4 months on dual antiplatelet therapy she expectorated blood when coughing. A lung X-ray and CT scan revealed numerous lung nodules later diagnosed as unclassified pleomorphic and spindle cell malignant solid neoplasm. The patient died following multiple brain metastasis.. Female gender, duration of prasugrel exposure, rare unclassified neoplasm pathology type and a tumor of a highly metastatic and aggressive nature in the index patient should be regarded with caution. The effects of novel antiplatelet agents on the onset of cancer should be tested in future mega-trials.

Topics: Aged; Aspirin; Brain Neoplasms; Carcinoma; Clinical Trials, Phase III as Topic; Clopidogrel; Colonic Neoplasms; Coronary Stenosis; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Drug Therapy, Combination; Drug-Eluting Stents; Fatal Outcome; Female; Humans; Lung Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Risk Factors; Thiophenes; Ticlopidine; Time Factors