Objective To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation.Design Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)—a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011.Participants 18 201 ARISTOTLE trial participants.Interventions In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years. Main outcome measures Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country).Results Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin.Conclusions In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe.Trial registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984.

BackgroundOver the last decades important risk factors for gastrointestinal symptoms have shifted, which may have changed its population prevalence. The aim of this study was to assess the current prevalence of gastrointestinal symptoms, appraise associated factors and assess health-related quality of life in the general population.MethodsA total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Demographic characteristics, gastrointestinal symptoms, health-related quality of life, medication use and co-morbidity were reported. We used multivariable logistic regression analysis to determine factors associated with gastrointestinal symptoms.ResultsA total of 18,317 questionnaires were returned, and 16,758 were eligible for analysis. Prevalence of gastrointestinal symptoms was 26%. Most frequent symptoms were bloating (63%), borborygmi (60%) and flatulence (71%). Female gender (adjusted OR (aOR) 1.59, 95% CI 1.43–1.77), asthma/COPD (aOR 1.47, 95% CI 1.21–1.79), use of paracetamol (aOR 1.33, 95% CI 1.20–1.47), antidepressants (aOR 1.56, 95% CI 1.22–2.00) and acid-suppressive medication were independently associated with presence of gastrointestinal symptoms. Age over 65 years (aOR 0.75, 95% CI 0.65–0.87), and use of statins (aOR 0.75, 95% CI 0.61–0.93) were associated with a lower prevalence of gastrointestinal symptoms. Respondents with gastrointestinal symptoms had a lower mean health-related quality of life of 0.81 (SD = 0.21) compared to 0.92 (SD = 0.14) for persons without gastrointestinal symptoms (P<0.01).ConclusionsPrevalence of gastrointestinal symptoms in the Dutch community is high and associated with decreased health-related quality of life.

Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. With the accumulating evidence from better designed, prospective clinical studies, an adverse effect of PPI use on clinical outcome in patients on clopidogrel cannot be substantiated. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomised data.

To cite this article: Jaspers Focks J, van Vugt SPG, Albers-Akkers MTH, Lamfers EJP, Bloem-de Vries LM, Verheugt FWA, Brouwer MA.Low performance of bleeding risk models in the very elderly with atrial fibrillation using vitamin K antagonists. J Thromb Haemost 2016; 14: 1715-24.See also Lip GYH, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. This issue, pp 1711-4. Essentials• Under-treatment of oral anticoagulation in the elderly with atrial fibrillation is common.• As bleeding prediction is challenging, we compared HAS-BLED, ATRIA and HEMORR 2 HAGES.• All three were associated with major bleeding in the elderly, but with poor predictive abilities.• Future studies with focus on elderly-specific risk factors for bleeding are warranted.Summary. Background: Anticipated bleeding complications contribute to underuse of oral anticoagulants, especially in elderly patients with atrial fibrillation (AF). Bleeding risk models could provide guidance; however, these were developed in the general AF population. Objective: To study and compare the performance of the HAS-BLED, ATRIA and HEMORR 2 HAGES for major bleeding in very elderly AF patients. Methods: Subjects were a random sample (N = 1157) of AF patients ≥ 80 years using a vitamin-K antagonist with prospective clinical follow-up from 2011 to 2014. The primary outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). Results: Patients aged 84 years (median; 25th-75th 82-87) were classified as low risk by HAS-BLED (25.2%), ATRIA (59.6%) and HEMORR 2 HAGES (23.3%). Three-year rates of major, clinically relevant and any bleeding were 6.7%, 28.3% and 42.3%, respectively. We observed a statistically significant association for all models with major bleeding, but discriminatory abilities were rather poor (Cstatistics < 0.60) without clear superiority for any of the three. Only two (anemia and antiplatelet therapy) of the various classical risk factors were associated with bleeding. An estimated risk-benefit profile indicated a favorable trade-off for oral anticoagulation in this specific cohort (number needed to treat, 22; number needed to harm, 91). Conclusions: In this large prospective cohort of very elderly AF patients, the currently used bleeding risk scores were all associated with major bleeding, but with poor predictive abilities. Use of the ATRIA model may inadvertently result in less attention being paid to modifiable risk factors in this particular population. In light of the issues of under-treatment and the suggested favorable risk-benefit profile, future models with incorporation of elderly-specific risk factors may provide more guidance in this growing population of AF patients.

Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

Prevalence of gastrointestinal symptoms was high in both prescribed and OTC NSAID users, emphasising the side effects of both types of NSAIDs. PPI co-prescription rates in NSAID users at risk for gastrointestinal complication were low.

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Although homocysteine is generally considered the aminothiol of interest with respect to cardiovascular disease, in our prospective study, only cysteine and glutathione appeared independently associated with recurrent atherothrombotic events. Moreover, we showed that an imbalance in the combination of aminothiols could be of more importance than investigating the individual metabolites.