prasugrel-hydrochloride and Neoplasms

Thienopyridines are a class of antiplatelet drugs widely used in cardiovascular disease prevention and treatment. A recent concern has come to light regarding the safety of thienopyridines because of the possible risk of malignancy. We therefore performed a systematic review and meta-analysis to evaluate the association between thienopyridine exposure and malignancy.. We searched the MEDLINE and EMBASE databases in March 2016 for studies that evaluated incident cancer and cancer mortality with and without exposure to thienopyridines. Relevant studies were identified, and data were extracted and analysed using random-effects meta-analysis.. A total of nine studies (six randomised controlled trials and three cohort studies) that included 282,084 participants were included. The cancer event rate with clopidogrel and prasugrel was 3.25% and 1.58% respectively. When compared with standard aspirin or placebo, thienopyridines are not significantly associated with cancer mortality and event rate (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.80-1.56, n = 3; and OR 0.92, 95% CI 0.52-1.64, n = 2, respectively. Further analyses examining clopidogrel showed no significant association with cancer event rate or malignancy-related death. When comparing prasugrel with clopidogrel, no significant association was noted for cancer event rate (OR 1.10, 95% CI 0.89-1.37, n = 2]. Subanalyses according to cancer location showed that thienopyridines are not significantly associated with malignancy mortality and/or incidence.. Our results suggest that there is currently insufficient evidence to suggest that thienopyridine exposure is associated with an increased risk of cancer event rate or mortality.

Topics: Aspirin; Clopidogrel; Humans; Incidence; Neoplasms; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Randomized Controlled Trials as Topic; Risk; Thienopyridines; Ticlopidine

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

Topics: Acute Coronary Syndrome; Humans; Incidence; Neoplasms; Periodicals as Topic; Piperazines; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Risk Factors; Thiophenes; United States

Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS.. The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79).. Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel.. ClinicalTrials.gov identifier: NCT00699998.

Topics: Acute Coronary Syndrome; Aged; Clopidogrel; Drug Therapy, Combination; Female; Hemorrhage; Humans; Long-Term Care; Male; Neoplasms; Non-ST Elevated Myocardial Infarction; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Ticlopidine; Treatment Outcome

Designing of smart clinical trials is critical for regulatory approval and future drug utilization. Importantly, trial design should be reconsidered if the interim analyses suggest unexpected harm, or conflicting results were yielded from the other trials within the same therapeutic area. With regard to antiplatelet agents, the perfect example is redesigning of the ongoing PRoFESS trial by eliminating aspirin from clopidogrel arm after the earlier MATCH trial results became available. The goal was to aseess the unchanged TRACER trial design in light of the evidence yielded from the earlier completed TRITON trial. TRACER was designed as a triple versus dual antiplatelet trial in NSTEMI patients with no previous long-term outcome data supporting such aggressive strategy. TRITON data represented dual versus dual antiplatelet therapy, and became available before TRACER enrollment starts revealing prasugrel front-loaded early vascular benefit predominantly in STEMI patients with the growing over time bleeding and cancer risks. Moreover, large prasugrel NSTEMI TRITON cohort exhibited trend towards excess mortality in experimental arm warning against aggressive TRACER design. The long-term TRITON results in general, and especially in the NSTEMI patients challenge unchanged TRACER trial design. Applying dual, rather than triple antiplatelet therapy protocol modification should be considered in TRACER to minimize bleeding, cancer, and non-cardiovascular death risks.

Topics: Acute Coronary Syndrome; Aspirin; Clinical Trials as Topic; Clopidogrel; Drug Evaluation; Drug Therapy, Combination; Hemorrhage; Humans; Lactones; Neoplasms; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyridines; Research Design; Ticlopidine

The impact of antithrombotics on cancer is currently under intense investigation because of the excess of solid cancers in trials after thienopyridines such as TRITON (prasugrel), DAPT (prasugrel and clopidogrel), PAR-1 thrombin antagonist in TRACER (vorapaxar), pyrimidines in PEGASUS (ticagrelor), and in APPRAISE-2 after apixaban. However, whether patient survival after solid cancer (SASC) in antithrombotic trials may be affected is unknown. We matched the 1-year SASC rate in antithrombotic trials reported by Food and Drug Administration with the census averages in Surveillance, Epidemiology, and End Results (SEER) Program by the US National Cancer Institute and World Health Organization (WHO) surveys. The Food and Drug Administration provided the SASC data for 3 trials with similar cancer survival of about 70% for the first year of follow-up in TRITON, APPRAISE-2, and ARISTOTEL. Adjusted cancers in TRITON with SEER (odds ratio 0.92; 95% confidence interval 0.53 to 1.59, p = 0.4351) and WHO (odds ratio 0.99; 95% confidence interval 0.57 to 1.7, p = 1.00) revealed very close if not identical SASC rates in antithrombotic trials compared to epidemiologic census estimates. In conclusion, SASC rates in patients enrolled in antithrombotic trials do not differ from SEER or World Health Organization averages.

Topics: Female; Humans; Male; Middle Aged; Neoplasms; Piperazines; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Risk Factors; SEER Program; Survival Rate; Thiophenes

Topics: Clinical Trials as Topic; Clopidogrel; Humans; Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

Topics: Animals; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Spleen; Stem Cells; T-Lymphocytes, Regulatory; Thiophenes

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Aspirin; Cardiovascular Diseases; Causality; Clinical Trials as Topic; Combined Modality Therapy; Coronary Thrombosis; Drug Administration Schedule; Drug Therapy, Combination; Hemorrhage; Humans; Myocardial Infarction; Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Thiophenes; United States; United States Food and Drug Administration

(1) For patients with acute coronary syndromes who have undergone percutaneous angioplasty and stenting, the best-assessed treatment for preventing relapses is a combination of aspirin and clopidogrel; (2) Prasugrel, an antiplatelet drug belonging the same chemical class as clopidogrel, is authorized in the EU for use in this indication; (3) Clinical evaluation is based on a randomized double-blind trial comparing prasugrel + aspirin versus clopidogrel + aspirin in 13 608 patients with acute coronary syndromes, half of whom were treated for at least 15 months. Prasugrel did not reduce overall mortality (about 3%) or the incidence of non-fatal stroke after 15 months (1% of patients). The only advantage reported with prasugrel was a significant reduction in the risk of non-fatal myocardial infarction (7.3% versus 9.5%); (4) In this trial, bleeding events, excluding those related to revascularisation procedures, were more frequent in the prasugrel group than in the clopidogrel group (2.4% versus 1.8%). Haemorrhages associated with revascularisation were also significantly more numerous with prasugrel (11.3% and 3.6%); (5) Subgroup analyses suggest that the risk-benefit balance of prasugrel is unfavourable in patients weighing less than 60 kg, patients over 75 years of age, and patients with a history of transient ischaemic attack or stroke; (6) The trial comparing prasugrel versus clopidogrel, as well as some animal studies, raise the possibility that prasugrel might increase the risk of cancer. In the main trial, prasugrel caused fewer cases of neutropenia than clopidogrel, but more cases of respiratory failure, hypotension and atrial flutter were observed; (7) In practice, for secondary prevention in patients with acute coronary syndromes treated with angioplasty and stenting, the risk-benefit balance of prasugrel, used in combination with aspirin, appears to be no better than that of clopidogrel + aspirin.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Cardiovascular Diseases; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Drug-Eluting Stents; Europe; Hemorrhage; Humans; Ischemic Attack, Transient; Myocardial Infarction; Neoplasms; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2; Recurrence; Stents; Stroke; Thiophenes; Ticlopidine; Treatment Outcome