Precision medicine and adverse drug reactions related to cardiovascular drugs

Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient’s genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The identification of specific variants associated with adverse drug effects aims to predict those at greatest risk of harm, allowing alternative therapies to be given. This review will explore current guidance available for pharmacogenomic-based prescribing as well as exploring the potential implementation of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records will be discussed to help facilitate the integration of pharmacogenomics into primary care, the heartland of prescribing

Pharmacy-led implementation of evidence based medicine in primary care : Evaluating Diuretics in Usual Care study (EVIDENCE)

Introduction Obtaining evidence of comparative effectiveness and safety of widely prescribed drugs in a timely cost-effective way is emerging as a major global challenge for healthcare systems. The Evaluating Drugs in Normal Care (EVIDENCE) programme addresses this challenge through novel methodology. We describe an exemplar pilot study comparing thiazide type diuretics for hypertension. Method Patients prescribed either indapamide or bendroflumethiazide for hypertension were identified in each primary care practice recruited. Random allocation of a prescribing policy for one or other of these drugs was then applied to the whole practice and where required repeat prescriptions were switched to comply with randomised policy. Patients were informed of the potential switch by letter with the option to discuss further with the study team and/or opt-out of the switch. Routinely collected hospitalization and death data in NHS will be used to compare cardiovascular event rates between the two policies. Results We found bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs despite recent NICE preference for indapamide. 29 primary care practices in 5 Scottish NHS boards were recruited and 14 randomised to indapamide and 15 to bendroflumethiazide creating a study population of 5985 patients. Less than 0.23% of patients opted out. Conclusion This pilot study demonstrated the feasibility and cost efficiency of the EVIDENCE approach. A relatively large study was generated rapidly with negligible disruption to practice workflows. EVIDENCE methodology offers a novel way to compare the effectiveness of a wide range of medicines where there is clinical equipoise.Non peer reviewe

Retinal Vascular Measures from Diabetes Retinal Screening Photographs and Risk of Incident Dementia in Type 2 Diabetes:A GoDARTS Study

OBJECTIVE: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. RESEARCH DESIGN AND METHODS: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox’s proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. RESULTS: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08–1.26) and AD (HR 1.33; 1.16–1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74–0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07–1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83–0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78–0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. CONCLUSIONS: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be amore limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching

Competing risks analysis for neutrophil to lymphocyte ratio as a predictor of diabetic retinopathy incidence in the Scottish population

Background: Diabetic retinopathy (DR) is a major sight-threatening microvascular complication in individuals with diabetes. Systemic inflammation combined with oxidative stress is thought to capture most of the complexities involved in the pathology of diabetic retinopathy. A high level of neutrophil–lymphocyte ratio (NLR) is an indicator of abnormal immune system activity. Current estimates of the association of NLR with diabetes and its complications are almost entirely derived from cross-sectional studies, suggesting that the nature of the reported association may be more diagnostic than prognostic. Therefore, in the present study, we examined the utility of NLR as a biomarker to predict the incidence of DR in the Scottish population.Methods: The incidence of DR was defined as the time to the first diagnosis of R1 or above grade in the Scottish retinopathy grading scheme from type 2 diabetes diagnosis. The effect of NLR and its interactions were explored using a competing risks survival model adjusting for other risk factors and accounting for deaths. The Fine and Gray subdistribution hazard model (FGR) was used to predict the effect of NLR on the incidence of DR.Results: We analysed data from 23,531 individuals with complete covariate information. At 10 years, 8416 (35.8%) had developed DR and 2989 (12.7%) were lost to competing events (death) without developing DR and 12,126 individuals did not have DR. The median (interquartile range) level of NLR was 2.04 (1.5 to 2.7). The optimal NLR cut-off value to predict retinopathy incidence was 3.04. After accounting for competing risks at 10 years, the cumulative incidence of DR and deaths without DR were 50.7% and 21.9%, respectively. NLR was associated with incident DR in both Cause-specific hazard (CSH = 1.63; 95% CI: 1.28–2.07) and FGR models the subdistribution hazard (sHR = 2.24; 95% CI: 1.70–2.94). Both age and HbA 1c were found to modulate the association between NLR and the risk of DR.Conclusions: The current study suggests that NLR has a promising potential to predict DR incidence in the Scottish population, especially in individuals less than 65 years and in those with well-controlled glycaemic status.</p