Hilary Wynne

Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation

Evidence suggests that alterations in the dietary intake of vitamin K can affect anticoagulation response to warfarin. It is possible that a low and erratic intake of dietary vitamin K is at least partly responsible for the variable response to warfarin in patients with unstable control of anticoagulation. Twenty-six patients with unstable and twenty-six with stable control of anticoagulation completed dietary records of all foods and drinks consumed on a daily basis for two consecutive weeks. The mean daily intake of vitamin K in unstable patients was considerably lower than that for stable patients during the study period (29+/-17 microg v . 76+/-40 microg). The logarithm of vitamin K intake was consistently and significantly lower in the unstable patients than the stable patients over the two week period (5.9+/-0.4 microg v. 6.9+/-0.5 microg; p<0.001; 95% CI: 0.7-1.2). Changes in vitamin K intake between weeks 1 and 2 of the study were negatively correlated with changes in International Normalised Ratio (INR) amongst the unstable patients, however this failed to reach significance (r=-0.25; p=0.22). Daily supplementation with oral vitamin K in unstable patients could lead to a more stable anticoagulation response to warfarin.

Pharmacogenetics of Warfarin

Warfarin is a drug with a narrow therapeutic index and a wide interindividual variability in dose requirement. Because it is difficult to predict an accurate dose for an individual, patients starting the drug are at risk of thromboembolism or bleeding associated with underdosing or overdosing, respectively. Single nucleotide polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) genes have been shown to have a significant effect on warfarin dose requirement. Other genes mediating the action of warfarin make either little or no contribution to dose requirement. Although the polymorphisms in CYP2C9 and VKORC1 explain a significant proportion of the interindividual variability in warfarin dose requirement, currently available evidence based on a few small studies relating to the use of pharmacogenetics-guided dosing in the initiation of warfarin therapy has not shown improved outcomes in either safety or efficacy of therapy. Better clinical evidence of beneficial effects on patient outcome, particularly at the extremes of the dose requirements in geographically and ethnically diverse patient populations, is needed before the role of a pharmacogenomic approach to oral anticoagulation therapy in clinical practice can be established.

Drug treatment in an ageing population: Practical implications

The population of the industrialised nations is ageing. By 2020 those of 65 years and older will constitute nearly 17% of the US population; it is predicted that the proportion of the population aged 80 years and over will then range from 3.5 to 6.5%, around the world. Those over 65, due to age-related chronic disease and more prophylactic prescribing, receive a disproportionate number of drugs; in the UK for example, 45% of the total prescriptions dispensed. Older patients may benefit from prophylactic treatments to a greater extent than younger people because of a higher absolute risk of disease and it is therefore important that they are not inappropriately denied these. However, it is also important that, as each additional drug prescribed brings an increased risk of an adverse drug effect, prescribers have enough knowledge of pharmacological issues in old age to enable them to weigh up these conflicting pressures to arrive at good prescribing decisions.

THE EFFECT OF STABILITY OF ORAL ANTICOAGULANT THERAPY UPON PATIENT‐PERCEIVED HEALTH STATUS AND QUALITY OF LIFE

during the last 9 months. Her Mini-Mental State Examination (MMSE) score was 17 of 30. The laboratory findings (Table 1) revealed a macrocytic anemia, a low serum albumin level, and a vitamin B 12 deficiency. Tests for anti-intrinsic factor antibodies and antigastric parietal cell antibodies were negative, but tests for antiendomysium, antitransglutaminase, and antigliadin antibodies were highly positive. A small intestine biopsy was performed, and histological analysis demonstrated characteristic changes of CD. A gluten-free diet (GFD) and parenteral vitamin B 12 were initiated. Adherence to the diet appeared to be good. Clinically, her weight progressively normalized (Table 1), and the anorexia and abdominal pain disappeared in less than a month. Concurrently, a striking regression of neuropsychiatric symptoms was observed: mental confusion, hallucinations, withdrawal attitude, and paranoid delirium disappeared in 3 months. Moreover, memory disturbances slowly regressed (MMSE was 27 of 30 at 12 months on GFD). Six months later, serological markers of CD were negative, and all other laboratory findings were corrected. Finally, normalization of histological findings of a small bowel biopsy at 1 year on GFD was concordant with clinical evolution. Neurological and psychiatric symptoms (cerebellar ataxia, epilepsy, dementia) are unusual manifestations of CD 1,2 that lead to a delay in diagnosis. We report the case of CD revealed in a 76-year-old woman by neuropsychiatric symptoms. Pathophysiology of such clinical signs remain to be determined, but the role of an eventual tissuespecific transglutaminase, like in dermatitis herpetiformis, 3 may be suggested. Vitamin B 12 deficiency has been associated with hematological, neurological,and psychiatric disorders. Although the terminal ileum is relatively spared in CD, vitamin B 12 deficiency is rather common in untreated CD patients. 3 Vitamin B 12 concentrations usually become normal on a GFD alone, but symptomatic patients, like ours, may require supplementation. 3 CD is not only a childhood disease. Hankey et al. 4 described 42 patients with CD diagnosed at age 60 and older, after many years with unexplained symptoms and missed diagnoses. It is now apparent that CD is underdiagnosed and that its clinical features have changed in children and adults. 5 Resolution of symptoms and improvement of quality of life can be obtained with a GFD, even in the elderly. It seems clear that early screening for CD should be proposed on a large scale using serological tests, even though small bowel biopsy sampling still remains necessary for diagnosis. 6

Effect of provision of the NHS NPSA oral anticoagulant therapy patient information pack upon patients’ knowledge and anticoagulant control

1 Smith NL, Chen MH, Dehghan A, Strachan DP, Basu S, Soranzo N, HaywardC,Rudan I, Sabater-LlealM,Bis JC, deMaatMP,RumleyA, Kong X, Yang Q, Williams FM, Vitart V, Campbell H, Malarstig A, WigginsKL,vanDuijnCM et al.Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121: 1382–92. 2 Kraaijenhagen RA, in t Anker PS, Koopman MM, Reitsma PH, Prins MH, van den Ende A, Buller HR. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5–9. 3 Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep vein thrombosis. Lancet 1995; 345: 152–5. 4 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Tracy RP, Aleksic N, Folsom AR. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636–42. 5 Tregouet DA, Heath S, Saut N, Biron-Andreani C, Schved JF, Pernod G, Galan P, Drouet L, Zelenika D, Juhan-Vague I, Alessi MC, Tiret L, Lathrop M, Emmerich J, Morange PE. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 2009; 113: 5298–303.

Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England

BACKGROUNDnnovel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult.nnnSETTINGnthe Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients.nnnOBJECTIVESnto examine anticoagulation stability and costs of monitoring.nnnSUBJECTSnthree hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service.nnnMETHODSnage, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed.nnnRESULTSnhome-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients.nnnCONCLUSIONSnfurther exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age.

Impact of age on long‐term anticoagulation and how gender and monitoring setting affect it: implications for decision making and patient management

AIMSnStabilization of anticoagulation control is seminal to reducing the risk of adverse effects of vitamin K antagonists. Reliable information on how ageing influences this is lacking. We set out to assess the true age-related changes in anticoagulation control, how gender and patient setting influence this, and the possible implications of these for patient outcomes and management.nnnMETHODSnIn atrial fibrillation (AF) patients of a unified anticoagulant service monitoring patients in general practice or hospital-based clinics and housebound patients at home, international normalized ratio (INR) and warfarin dose data between 2000 and 2013 were extracted via the DAWN dosing program. Anticoagulation control was assessed by calculating percentage time spent within target INR (TTR).nnnRESULTSnA total of 2094 AF patients [938 (44.8%) in general practice (GP) and 531 (25.4%) in hospital (H)-based clinics and 625 (29.8%) through the domiciliary service (D)] were evaluated. The frequency of warfarin dose changes and INR monitoring events declined until about age 67, then increased as patients got older. The TTR according to age was significantly lower and the probability of having a TTRxa0≤65% according to age was higher for D than for H and GP, and females had a greater probability of having a TTR ≤65% than age-matched males.nnnCONCLUSIONnIdentification of factors underlying poorer anticoagulation control in older housebound patients and the introduction of effective modifications to improve the clinical effectiveness of anticoagulation in such patients is needed.

Influence of CYP2C9 polymorphism on the fall in International Normalized Ratio in patients interrupting warfarin therapy before elective surgery

Patients on warfarin are normally required to stop treatment for a fixed number of days prior to an invasive procedure. However, the anticoagulant activity of warfarin subsides at different rates among different patients.

The impact of genetics on the management of patients on warfarin awaiting surgery

Two older patients with atrial fibrillation, receiving warfarin for thromboembolic prophylaxis, with a target range of 2.0-3.0, were significantly over anticoagulated prior to elective intervention, in spite of having adhered to the standard protocol of 5 days of warfarin interruption. Neither patient had any abnormality of liver function nor was taking any interacting drug known to inhibit warfarin metabolism or affect sensitivity to warfarin. Both had variant cytochrome P2C9 (CYP2C9) alleles which reduce the metabolic capacity of the CYP2C9 enzyme responsible for the metabolism of the S-warfarin enantiomer. Need for preoperative administration of vitamin K or postponement of an operation because of an INR >1.5 could be explained by variant alleles for CYP2C9 and age.

Effect of genetic and patient factors on warfarin pharmacodynamics following warfarin withdrawal: Implications for patients undergoing surgery

INTRODUCTIONnWarfarin therapy is stopped for a fixed period prior to surgery to minimise risk of perioperative bleeding. However, anticoagulation subsides at varying rates among different patients. We evaluated the influence of genetic (CYP2C9 and VKORC1), patient and clinical factors on warfarin clearance and the decline in INR following warfarin withdrawal.nnnMATERIALS AND METHODSn131 patients completing a course of warfarin provided blood samples over 9u202fdays for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations.nnnRESULTSnS-warfarin clearance was significantly lower in patients with either CYP2C9 single (*2 or *3) or double (*2*2 or *2*3) variant alleles compared to those with wild-type genotype (Pu202f<u202f0.001). Regression analysis revealed that patient age (Pu202f=u202f0.037) and CYP2C9 *2*2 & *2*3 genotype (Pu202f=u202f0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5).nnnCONCLUSIONSnThe inter-individual variability in the time needed for normal coagulation to resume following warfarin withdrawal is influenced, in the main, by variance in S-warfarin clearance, which in turn is affected by CYP2C9 polymorphism and age. Cost-effectiveness of pharmacogenetics-based algorithms incorporating CYP2C9 genotype and patient age could be increased if used not only to guide dosing decisions but also estimation of the correct length of time needed for individual patients to stop taking warfarin prior to surgery.