Aspirin and the Primary Prevention of Cardiovascular Diseases. An Approach Based on Individualized, Integrated Estimation of Risk

While the use of aspirin in the secondary prevention of cardiovascular (CVD) is well established, aspirin in primary prevention is not systematically recommended because the absolute CV event reduction is similar to the absolute excess in major bleedings. Recently, emerging evidence suggests the possibility that the assumption of aspirin, may also be effective in the prevention of cancer. By adding to the CV prevention benefits the potential beneficial effect of aspirin in reducing the incidence of mortality and cancer could tip the balance between risks and benefits of aspirin therapy in the primary prevention in favour of the latter and broaden the indication for treatment with in populations at average risk. While prospective and randomized study are currently investigating the effect of aspirin in prevention of both cancer and CVD, clinical efforts at the individual level to promote the use of aspirin in global (or total) primary prevention could be already based on a balanced evaluation of the benefit/risk ratio

Aspirin-Induced Mortality in AedesaegyptiMosquitoes

The Aedes aegypti mosquito is a vector for many dangerous diseases including yellow fever, Zika, Chikungunya, and Dengue viruses! Currently, the best method for suppressing infection with these viruses is by controlling their arthropod vectors, however the continual use of conventional insecticides to control Ae. aegypti mosquitoes has led to the development of significant levels of resistance to these chemicals. Accordingly, new methods are needed. Anecdotal evidence has suggested that mosquitoes may be sensitive to treatment with aspirin or its metabolites in a blood meal. Previous studies with aspirin in insects have mainly focused on the ability of aspirin to enhance longevity and lifespan in Drosophila melanogaster and crickets2.4, but one study showed that aspirin in water where larvae are developing causes significant mortality and signs of neurotoxicity. While treating larvae in this manner is not practical for vector control, this result, in addition to the anecdotal evidence, prompted the question of whether aspirin consumed in a blood meal can cause mortality in adult mosquitoes. Accordingly, we fed adult female Ae. aegypti mosquitoes differing concentrations of aspirin in human blood and measured mortality for four days following the blood meal. The concentrations chosen correspond to plasma concentrations of aspirin in humans who have consumed 100 mg (a baby aspirin), 1 g (normal adult dose), or 10 g (overdose), respectively. Our results indicate that these concentrations of aspirin are insufficient to cause significant mortality in the mosquitos. Although unsuccessful, modification of our methods, use of a different mosquito species, or use of aspirin metabolites in our bioassays may yet show a significant impact of aspirin consumption on mosquito survival

Nasal lysine aspirin challenge in the diagnosis of aspirin - exacerbated respiratory disease

Background Aspirin-exacerbated respiratory disease is under-diagnosed and therefore effective and inexpensive therapy with aspirin desensitization is rarely performed. Methods We present an audit of 150 patients with difficult to treat nasal polyposis, 132 of whom also had asthma, 131 of whom underwent challenge with the only soluble form of aspirin, lysine aspirin (LAS), to confirm or exclude the diagnosis of aspirin-exacerbated respiratory disease (AERD). Results One hundred patients proved positive on nasal challenge, 31 who were negative went onto oral LAS challenge and a further 14 gave positive results, leaving 17 who were negative to a dose equivalent to over 375 mg of aspirin. Nineteen were not challenged because of contraindications. With the exception of one patient who developed facial angioedema and two patients with > 20% drop in FEV1 (following nasal plus oral challenge) no other severe adverse events occurred. No hospitalization was required for these three patients. Nasal inspiratory peak flow monitoring was less sensitive to obstruction caused by aspirin than was acoustic rhinometry – which should be employed when aspirin challenge is an outpatient procedure. Conclusions Provided patients are carefully chosen and monitored LAS challenge is suitable for ENT day case practice where respiratory physician help with asthma is available and should reduce the under-diagnosis of this condition

Aspirin-dependent effects on purinergic P2Y1 receptor express

Chronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor. We hypothesized that recovery of ADP-induced platelet activation could be attributed to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients. DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors, in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks. Platelets obtained from patients who were on aspirin for more than 2 months had increased P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment for less than a month. Overall, our results suggest that aspirin induces genomic changes in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation. Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological inhibition seems not to be receptor specific, but may involve other receptors with the same biochemical pathway

Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin

BACKGROUND: Pneumonia is complicated by high rate of mortality and cardiovascular events (CVEs). The potential benefit of aspirin, which lowers platelet aggregation by inhibition of thromboxane A2 production, is still unclear. The aim of the study was to assess the impact of aspirin on mortality in patients with pneumonia. METHODS AND RESULTS: Consecutive patients admitted to the University-Hospital Policlinico Umberto I (Rome, Italy) with community-onset pneumonia were recruited and prospectively followed up until discharge or death. The primary end point was the occurrence of death up to 30 days after admission; the secondary end point was the intrahospital incidence of nonfatal myocardial infarction and ischemic stroke. One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow-up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%; P<0.001) were aspirin nonusers. Overall, nonfatal CVEs occurred in 7% of patients, 8.3% in nonaspirin users, and 4.9% in aspirin users (odds ratio, 1.77; 95% confidence interval, 1.03 to 3.04; P=0.040). The Cox regression analysis showed that pneumonia severity index (PSI), severe sepsis, pleural effusion, and PaO(2)/FiO(2) ratio <300 negatively influenced survival, whereas aspirin therapy was associated with improved survival. Compared to patients receiving aspirin, the propensity score adjusted analysis confirmed that patients not taking aspirin had a hazard ratio of 2.07 (1.08 to 3.98; P=0.029) for total mortality. CONCLUSIONS: This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia

Is clopidogrel better than aspirin following breakthrough strokes while on aspirin? A retrospective cohort study.

ObjectiveThere is insufficient evidence on which to base a recommendation for optimal antiplatelet therapy following a stroke while on aspirin. The objective was to compare clopidogrel initiation vs aspirin reinitiation for vascular risk reduction among patients with ischaemic stroke on aspirin at the time of their index stroke.DesignRetrospective.SettingWe conducted a nationwide cohort study by retrieving all hospitalised patients (≥18 years) with a primary diagnosis of ischaemic stroke between 2003 and 2009 from Taiwan National Health Insurance Research Database.ParticipantsAmong 3862 patients receiving aspirin before the index ischaemic stroke and receiving either aspirin or clopidogrel after index stroke during follow-up period, 1623 were excluded due to a medication possession ratio &lt;80%. Also, 355 were excluded due to history of atrial fibrillation, valvular heart disease or coagulopathy. Therefore, 1884 patients were included in our final analysis.InterventionsPatients were categorised into two groups based on whether clopidogrel or aspirin was prescribed during the follow-up period. Follow-up was from time of the index stroke to admission for recurrent stroke or myocardial infarction, death or the end of 2010.Primary and secondary outcome measuresThe primary end point was hospitalisation due to a new-onset major adverse cardiovascular event (MACE: composite of any stroke or myocardial infarction). The leading secondary end point was any recurrent stroke.ResultsCompared to aspirin, clopidogrel was associated with a lower occurrence of future MACE (HR=0.54, 95% CI 0.43 to 0.68, p&lt;0.001, number needed to treat: 8) and recurrent stroke (HR=0.54, 95% CI 0.42 to 0.69, p&lt;0.001, number needed to treat: 9) after adjustment of relevant covariates.ConclusionsAmong patients with an ischaemic stroke while taking aspirin, clopidogrel initiation was associated with fewer recurrent vascular events than aspirin reinitiation

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Aspirin inhibits the acute venodilator response to furosemide in patients with chronic heart failure

OBJECTIVES: We sought to determine the effect of aspirin on the venodilator effect of furosemide in patients with chronic heart failure (CHF) BACKGROUND: Furosemide has an acute venodilator effect preceding its diuretic action, which is blocked by nonsteroidal anti-inflammatory drugs. The ability of therapeutic doses of aspirin to block this effect of furosemide in patients with CHF has not been studied. For comparison, the venodilator response to nitroglycerin (NTG) was also studied. METHODS: Eleven patients with CHF were randomized to receive placebo, aspirin at 75 mg/day or aspirin at 300 mg/day for 14 days in a double-blind, crossover study. The effect of these pretreatments on the change in forearm venous capacitance (FVC) after 20 mg of intravenous furosemide was measured over 20 min by using venous occlusion plethysmography. In a second study, the effect of 400 μg of sublingual NTG on FVC was documented in 11 similar patients (nine participated in the first study). RESULTS: Mean arterial pressure, heart rate and forearm blood flow did not change in response to furosemide. After placebo pretreatment, furosemide caused an increase in FVC of 2.2% (95% confidence interval [CI] −0.9% to 5.2%; mean response over 20 min). By comparison, FVC fell by −1.1% (95% CI −4.2% to 1.9%) after pretreatment with aspirin at 75 mg/day, and by −3.7% (95% CI −6.8% to −0.7%) after aspirin at 300 mg/day (p = 0.020). In the second study, NTG increased FVC by 2.1% (95% CI −1.6% to 5.8%) (p = 0.95 vs. furosemide). CONCLUSIONS: In patients with CHF, venodilation occurs within minutes of the administration of intravenous dose of furosemide. Our observation that aspirin inhibits this effect further questions the use of aspirin in patients with CHF

Comparison of Risk of Recrudescent Fever in Children With Kawasaki Disease Treated With Intravenous Immunoglobulin and Low-Dose vs High-Dose Aspirin

Importance: Timely initiation of intravenous immunoglobulin plus aspirin is necessary for decreasing the risk of recrudescent fever and coronary artery abnormalities in children with Kawasaki disease (KD). The optimal dose of aspirin, however, remains unclear. Objective: To evaluate whether initial treatment with low-dose compared with high-dose aspirin in children with KD is associated with an increase in fever recrudescence. Design, Setting, and Participants: A retrospective cohort study of 260 children with KD at Riley Hospital for Children, Indianapolis, Indiana, between January 1, 2007, and December 31, 2018, was conducted. Children aged 0 to 18 years with a first episode of KD, identified by International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes treated within 10 days of symptom onset with high-dose intravenous immunoglobulin plus aspirin were eligible. Patients who received an alternative diagnosis, experienced a second episode of KD, did not receive intravenous immunoglobulin plus aspirin for initial treatment, were not treated within 10 days of symptoms, or had incomplete records were excluded. Exposures: High-dose (≥10 mg/kg/d) or low-dose (<10 mg/kg/d) aspirin therapy. Main Outcomes and Measures: The primary outcome was recrudescent fever necessitating retreatment of KD. The secondary outcomes were coronary artery abnormalities and hospital length of stay. Results: Among the 260 patients included, the median (interquartile range) age was 2.5 (1.6-4.3) years, 103 (39.6%) were girls, 166 (63.8%) were non-Hispanic white, 57 (21.9%) were African American, 22 (8.5%) were Asian, 11 (4.2%) were Hispanic, and 4 (1.5%) were of unknown race/ethnicity. One hundred-forty-two patients (54.6%) were treated with low-dose aspirin. There was no association between recrudescent fever and aspirin dose, with 39 children (27.5%) having recrudescent fever in the low-dose group compared with 26 children (22.0%) in the high-dose group (odds ratio [OR], 1.34; 95% CI, 0.76-2.37; P = .31), with similar results after adjusting for potential confounding variables (OR, 1.63; 95% CI, 0.89-2.97; P = .11). In a subset analysis of 167 children with complete KD, however, there was nearly a 2-fold difference in the odds of recrudescent fever with low-dose aspirin (OR, 1.87; 95% CI, 0.82-4.23; P = .14), although this difference did not reach statistical significance. In addition, no association was identified between treatment group and coronary artery abnormalities (low-dose, 7.4% vs high-dose, 9.4%; OR, 0.86; 95% CI, 0.48-1.55; P = .62) or median (interquartile range) length of stay (3 [3-5] days for both groups; P = .27). Conclusions and Relevance: In this study, low-dose aspirin for the initial treatment of children with KD was not associated with fever recrudescence or coronary artery abnormalities. Given the potential benefits, further study of low-dose aspirin to detect potentially clinically relevant outcome differences is warranted to inform treatment decisions and guideline development