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Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Kasner, SE, Swaminathan, B, Lavados, P, Sharma, M, Muir, K, Veltkamp, R, Ameriso, SF, Endres, M, Lutsep, H, Messé, SR, et al
The Lancet. Neurology. 2018;(12):1053-1060
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Abstract
BACKGROUND Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. METHODS NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. FINDINGS Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. INTERPRETATION Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. FUNDING Bayer and Janssen.
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Colorectal Cancer Screening and Prevention.
Wilkins, T, McMechan, D, Talukder, A
American family physician. 2018;(10):658-665
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Abstract
Colorectal cancer is a common cause of morbidity and mortality in the United States. Most colorectal cancers arise from preexisting adenomatous or serrated polyps. The incidence and mortality of colorectal cancer can be reduced with screening of average-risk adults 50 to 75 years of age. Randomized controlled trials show evidence of reduced colorectal cancer-specific mortality with guaiac-based fecal occult blood tests and flexible sigmoidoscopy. There are no randomized controlled trials on the effectiveness of colonoscopy to reduce colorectal cancer-specific mortality; however, several randomized controlled trials comparing colonoscopy with other strategies are in progress. The best available evidence supporting colonoscopy is from prospective cohort studies that demonstrate decreased incidence of colorectal cancer and colorectal cancer-related mortality in individuals undergoing colonoscopy. Other screening options include fecal immunochemical testing, computed tomographic colonography, and multitargeted stool DNA testing combined with fecal immunochemical testing. There is good evidence that aspirin, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and hormone therapy decrease the risk of colorectal cancer and adenomatous polyps, but potential harms limit their usefulness. There is good evidence that calcium supplementation, moderate dairy consumption, reduced red meat consumption, increased physical activity, decreased body mass index, and statin use decrease the risk of colorectal cancer and adenomatous polyps. Although increased alcohol intake and tobacco use are associated with an increased risk of colorectal cancer, there is no direct evidence that reducing alcohol consumption or smoking cessation decreases the risk.
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Comparison of Aspirin and Naoxintong Capsule () with Adjusted-Dose Warfarin in Elderly Patients with High-Risk of Non-Valvular Atrial Fibrillation and Genetic Variants of Vitamin K Epoxide Reductase.
Wang, H, Zhou, XK, Zheng, LF, Wu, XY, Chen, H
Chinese journal of integrative medicine. 2018;(4):247-253
Abstract
OBJECTIVE To compared the therapeutic effect of a Chinese patent medicine Naoxintong Capsule (, NXT) and aspirin with adjusted-dose warfarin in Chinese elderly patients (over 65 years) with nonvalvular atrial fibrillation (NVAF) and genetic variants of vitamin K epoxide reductase (VKORC1), who are at high-risk of thromboembolism. METHODS A total of 151 patients, with NVAF and AA genotype of VKORC1-1639 (a sensitive genotype to warfarin) and a CHA2DS2-VASc clinical risk score of 2 or above, were chosen for this study. Patients were randomized into two groups and orally treated with a combination of aspirin (100 mg/day) and NXT (1.6 g thrice a day) or adjusted-dose warfarin [international normalized ratio 2.0-3.0). The primary end points including ischemic stroke and death as well as the secondary end points including hemorrhage events were followed up for at least 1 year. RESULTS Baseline clinical data and the rates of primary end points were similar between groups. However, the rate of serious bleeding (secondary event) in the combination therapy group was lower than that in the adjusted-dose warfarin group (0% vs. 7.9%, odds ratio: 0.921, 95% confidence interval: 0.862-0.984, P=0.028). CONCLUSIONS Aspirin combined with NXT and warfarin displayed comparable rates of primary end point including ischemic stroke and all-cause death during the 1-year follow-up. However, as compared with warfarin, the combination therapy reduced the rate of serious bleeding. Therefore, aspirin combined with NXT might provide an alternative pharmacotherapy in preventing ischemic stroke for elderly patients with NAVF who cannot tolerate warfarin. (No. ChiCTR-TRC-13003596).
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Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans?
Pan, P, Huang, YW, Oshima, K, Yearsley, M, Zhang, J, Yu, J, Arnold, M, Wang, LS
International journal of molecular sciences. 2018;(1)
Abstract
Early inhibition of inflammation suppresses the carcinogenic process. Aspirin is the most commonly used non-steroid anti-inflammatory drugs (NSAIDs), and it irreversibly inhibits cyclooxygenase-1 and -2 (COX1, COX2). Multiple randomized clinical trials have demonstrated that aspirin offers substantial protection from colon cancer mortality. The lower aspirin doses causing only minimal gastrointestinal disturbance, ideal for long-term use, can achieve only partial and transitory inhibition of COX2. Aspirin's principal metabolite, salicylic acid, is also found in fruits and vegetables that inhibit COX2. Other phytochemicals such as curcumin, resveratrol, and anthocyanins also inhibit COX2. Such dietary components are good candidates for combination with aspirin because they have little or no toxicity. However, obstacles to using phytochemicals for chemoprevention, including bioavailability and translational potential, must be resolved. The bell/U-shaped dose-response curves seen with vitamin D and resveratrol might apply to other phytochemicals, shedding doubt on 'more is better'. Solutions include: (1) using special delivery systems (e.g., nanoparticles) to retain phytochemicals; (2) developing robust pharmacodynamic biomarkers to determine efficacy in humans; and (3) selecting pharmacokinetic doses relevant to humans when performing preclinical experiments. The combination of aspirin and phytochemicals is an attractive low-cost and low-toxicity approach to colon cancer prevention that warrants testing, particularly in high-risk individuals.
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Effects of Ramadan fasting on aspirin resistance in type 2 diabetic patients.
Bouida, W, Beltaief, K, Baccouche, H, Sassi, M, Dridi, Z, Trabelsi, I, Laaouiti, K, Chakroun, T, Hellara, I, Boukef, R, et al
PloS one. 2018;(3):e0192590
Abstract
AIMS: Ramadan fasting (RF) may affect aspirin resistance. We conducted this study in patients with cardiovascular risk (CVR) factors to assess the effect of RF on aspirin resistance and explore whether type 2 diabetes mellitus (DM) would influence this effect. METHODS A total of 177 stable patients with ≥2 CVR factors were recruited. All patients observed RF and were taking aspirin. Physical exam and standard biological tests including glycaemia and serum lipids data were performed before Ramadan (Pre-R), at the last week of Ramadan (R) and four weeks after the end of Ramadan (Post-R). In the same visits caloric intake was calculated and platelet reactivity to aspirin was assessed using Verify Now point-of-care assay. RESULTS In the overall population, there was no significant change in absolute aspirin reaction unit (ARU) values and in metabolic parameters. In DM patients (n = 127), ARU change from Pre-R values was+19.7 (p = 0.01) and +14.4 (p = 0.02) respectively at R and Post-R. During Ramadan, glycaemia, triglycerides, and cholesterol levels increased significantly and returned to Pre-R values thereafter. These changes were not observed in non-DM patients. CONCLUSIONS During RF aspirin resistance increased only in DM patients. This effect persisted one month after Ramadan. Simultaneous alteration of glycemic control and increase of serum lipids levels could potentially be a favorable factor. STUDY REGISTRATION The protocol was registered at clinicaltrials.gov under: NCT02720133.
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Aspirin exacerbated respiratory disease: Current topics and trends.
Rodríguez-Jiménez, JC, Moreno-Paz, FJ, Terán, LM, Guaní-Guerra, E
Respiratory medicine. 2018;:62-75
Abstract
Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets. In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option.
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[Aspirin and colorectal cancer].
Grancher, A, Michel, P, Di Fiore, F, Sefrioui, D
Bulletin du cancer. 2018;(2):171-180
Abstract
Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation.
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Thromboxane inhibition during concurrent therapy with low-dose aspirin and over-the-counter naproxen sodium.
Gurbel, PA, Bliden, KP, Zhu, J, Troullos, E, Centofanti, R, Jarvis, S, Venkataraman, P, Tantry, US
Journal of thrombosis and thrombolysis. 2018;(1):18-26
Abstract
UNLABELLED Aspirin is the dominant antiplatelet therapy for cardiovascular disease. Naproxen is frequently used in aspirin-treated patients and may influence the antiplatelet effect of aspirin. We evaluated the pharmacodynamic interaction (lower bound of the one-sided 95% CI for serum TxB2 inhibition < 95%) between 220 mg immediate-release naproxen sodium (once or twice daily) and 81 mg daily immediate release aspirin at various dosing intervals. There was no interaction during the first day of concurrent treatment. After 10 days, irrespective of the timing and dose of naproxen in relation to aspirin dosing, a pharmacodynamic interaction occurred which persisted after discontinuing naproxen. In the control group (aspirin alone), the lower bound for serum TxB2 inhibition was > 98% at all time points. The clinical relevance of these observations remains unknown and merits further investigation since over-the-counter naproxen is widely used to relieve pain by individuals taking low dose aspirin for cardioprotection. CLINICAL TRIAL REGISTRATION NCT02229461.
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Predictors of Mortality in Patients With Atrial Fibrillation (from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE A]).
Perera, KS, Pearce, LA, Sharma, M, Benavente, O, Connolly, SJ, Hart, RG, ,
The American journal of cardiology. 2018;(5):584-589
Abstract
The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4 < 25 kg/m2, 95% CI 1.3 to 1.6), diabetes mellitus, Latin American ethnicity (HR 1.4, 95% CI 1.1 to 1.6), previous stroke or transient ischemic attack, peripheral artery disease, increased resting heart rate (HR 1.3, 95% CI 1.1 to 1.4 per 30 bpm), lower diastolic blood pressure, coronary artery disease, heart failure, left ventricular systolic dysfunction, hemoglobin level of <13 mg/dl, and reduced estimated glomerular filtration rate. In conclusion, in this large clinical trial cohort of patients with AF, treatment with clopidogrel plus aspirin versus aspirin monotherapy did not affect all-cause mortality, vascular death, or nonvascular death. Novel independent predictors of increased mortality included lower diastolic blood pressure and Latin American ethnicity.
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Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas.
Passarelli, MN, Barry, EL, Zhang, D, Gangar, P, Rees, JR, Bresalier, RS, McKeown-Eyssen, G, Karagas, MR, Baron, JA
The British journal of dermatology. 2018;(2):337-344
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Abstract
BACKGROUND Aspirin may reduce the risk of several types of cancer. OBJECTIVES To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). METHODS BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. RESULTS One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7-17] for placebo, 16% (95% CI 11-21) for 81 mg aspirin daily and 15% (95% CI 10-20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93-2·26); HR for 81 mg daily 1·57 (95% CI 0·96-2·56); HR for 325 mg daily 1·33 (95% CI 0·80-2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (Pinteraction = 0·02 for 81 mg aspirin daily; Pinteraction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57-1·27). CONCLUSIONS Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC.