Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM ...is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.
Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists ...(of which warfarin is the most widely used and is used as the exemplar in this paper), and direct oral anticoagulants (DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban). This paper explores the recent advances and controversies in oral anticoagulation. While some commentators may favour a complete switchover to DOACs, this paper argues that warfarin still has a place in therapy, and a stratified approach that enables the correct choice of both drug and dose would improve both patient outcomes and affordability.
The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing ...with that of standard dosing on anticoagulation control in patients starting warfarin therapy.
We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.
A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).
Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).
Inter-individual variability in drug response, be it efficacy or safety, is common and likely to become an increasing problem globally given the growing elderly population requiring treatment. ...Reasons for this inter-individual variability include genomic factors, an area of study called pharmacogenomics. With genotyping technologies now widely available and decreasing in cost, implementing pharmacogenomics into clinical practice - widely regarded as one of the initial steps in mainstreaming genomic medicine - is currently a focus in many countries worldwide. However, major challenges of implementation lie at the point of delivery into health-care systems, including the modification of current clinical pathways coupled with a massive knowledge gap in pharmacogenomics in the health-care workforce. Pharmacogenomics can also be used in a broader sense for drug discovery and development, with increasing evidence suggesting that genomically defined targets have an increased success rate during clinical development.
Understanding the relationship between occupation and alcohol use offers opportunities to provide health promotion programmes based on evidence of need. We aimed to determine associations between ...occupation and heavy alcohol consumption in working individuals aged 40-69 years.
A cross-sectional study was conducted using 100,817 people from the UK Biobank: 17,907 participants categorised as heavy drinkers, defined as > 35 units/week for women and > 50 units/week for men, and 82,910 drinking controls. Prevalence ratios (PRs) and 95% CIs were calculated for gender-specific heavy drinking in 353 occupations using Standard Occupational Classification, V.2000.
Seventy-seven occupations were associated with level of alcohol consumption in drinkers. The largest ratios for heavy drinkers were observed for publicans and managers of licenced premises (PR = 2.81, 95%CI 2.52-3.14); industrial cleaning process occupations (PR = 2.09, 1.33-3.28); and plasterers (PR = 2.07, 1.66-2.59). Clergy (PR = 0.20, 0.13-0.32); physicists, geologists and meteorologists (PR = 0.40, 0.25-0.65); and medical practitioners (PR = 0.40, 0.32-0.50) were least likely to be heavy drinkers. There was evidence of gender-specific outcomes with the proportion of jobs associated with heavy drinking accounted for by skilled trade occupations being 0.44 for males and 0.05 for females, and 0.10 for males and 0.40 for females when considering managers and senior officials.
In the largest study of its kind, we found evidence for associations between a wider variety of occupations and the risk of heavy alcohol consumption than identified previously, particularly in females, although causality cannot be assumed. These results help determine which jobs and broader employment sectors may benefit most from prevention programmes.
Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of ...these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions.
About 1.4 British million people are at risk of strokes due to non-valvular atrial fibrillation (AF) necessitating long-term anticoagulation. The vitamin K antagonist, warfarin, has a long half-life ...and narrow therapeutic range necessitating regular monitoring and is a common cause of iatrogenic hospital admission. Direct-acting oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban and edoxaban are not required to have monitoring but are sensitive to changes in renal function and are associated with poorer adherence. There are good grounds to believe that DOACs are not always superior to warfarin in routine practice particularly with an older population. Much higher levels of therapeutic effectiveness can be achieved using a simple genotype guidance to identify those who are highly sensitive and by adoption of home monitoring. These adjustments could make warfarin the preferred drug for most people and would reduce the dramatic rise in health service expenditure.
Aspirin is one of the cornerstones of treatment for cardiovascular disease. However, some patients may be 'resistant' to its effect: this is associated with adverse cardiovascular outcomes and ...increased mortality. Measuring response to aspirin is often difficult and there is no accepted definition of aspirin resistance. Many assays are available to test aspirin sensitivity but most are not specific to aspirin and the degree of agreement between different assays is poor. Each assay has its own advantages and disadvantages, and there is currently no one assay that can be recommended for routine clinical practise. There are also many potential modifiers of aspirin response including aspirin dose, non-compliance, disease severity, genetic factors, inflammation, diabetes mellitus, hyperlipidaemia, smoking and interacting drugs. Treating the underlying cause may improve aspirin sensitivity but current data are contradictory with no large clinical trials that have addressed this. Further work is required in this area to determine whether and how aspirin resistance is important clinically, what the best measurement is phenotypically and how this should be used in clinical practise, and whether there are any genetic predisposing factors. This will require well designed prospective studies which take into account the numerous confounding factors that can modify aspirin resistance.
Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores ...correlate with irAE colitis outcomes.
A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed.
In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03).
CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.
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