Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients.

It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.

Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing.

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects [median (IQR) age: 83(75-87) vs 30(26-38) years] provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100-500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects [%change from baseline for Endogenous Thrombin Potential (ETP): - 35.0 ± 4.4 vs - 29.8 ± 7.4 nM*min; p = 0.002]. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation.

Validation of an algorithm to predict decline in INR following warfarin cessation in patients undergoing invasive procedures.

Patients on warfarin are required to withdraw from treatment for a fixed period (normally 5 days) prior to an invasive procedure. However, the anticoagulant effect of warfarin subsides at different rates among different patients, exposing some to increased risk of either thrombosis or bleeding. In a recent study in patients awaiting surgery, following warfarin cessation the INR declined slower over time in those with two CYP2C9 variant alleles, increasing age, weight and number of comorbidities and that INR decline was faster in those with higher maintenance INR value. Subsequently, we developed an algorithm which predicts INR decline in individual patients after 5 days of warfarin cessation. The current study validated the algorithm. An independent cohort of patients completing a short course of warfarin took part in the study. INR values for subsequent 9 days and CYP2C9 genotype were available. The predicted INR decline (INRday 1-INRday 5) was compared to the observed one (where an INR check on day 5 was unavailable, INR was estimated using a linear approximation model). There was a strong correlation between the decline in INR by day 5 and that predicted from the algorithm for the 117 patients (r = 0.949, p < 0.001). The algorithm was precise, with low degree of bias and variance of the prediction error. The algorithm can accurately predict the INR decline following warfarin cessation in individual adult patients. The use of this easily adoptable algorithm can reduce cancellation or delays of planned surgical procedures.

Individual and monitoring centre influences upon anticoagulation control of AF patients on warfarin: A longitudinal multi-centre UK-based study.

OBJECTIVES: Time within therapeutic INR range (TTR) predicts benefits/risk of warfarin therapy. Identification of individual- and centre-related factors that influence TTR, and addressing them to improve anticoagulation control, are important. This study examined the impact of individual and centre-related factors upon long-term anticoagulation control in atrial fibrillation patients in seven UK-based monitoring services. METHODS: Data between 2000 and 2014 on 25 270 patients (equating to 203 220 patient years) [18 120 (71.7%) in general practice, 2348 (9.3%) in hospital-based clinics and 4802 (19.0%) in domiciliary service] were analysed. RESULTS: TTR increased with increasing age, peaking around 77% at 70-75 years, and then declined, was lower in females than males, and in dependent home-monitored patients than those attending clinic (P < 0.0001). TTR, number of dose changes and INR monitoring events and the probability of TTR ≤ 65%, differed across the centres (P < 0.0001). CONCLUSIONS: Although all the participating centres ostensively followed a standard dosing algorithm, our results indicate that variations in practice do occur between different monitoring sites. We suggest feedback on TTR for individual monitoring sites gauged against the average values reported by others would empower the individual centres to improve quality outcomes of anticoagulation therapy by identifying and adjusting contributory factors within their management system.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P < 0·001). Individualised vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients.

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

AIMS: Stabilization 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. METHODS: In 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). RESULTS: A 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 TTR ≤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. CONCLUSION: Identification 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.

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.

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

BACKGROUND: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult. SETTING: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients. OBJECTIVES: to examine anticoagulation stability and costs of monitoring. SUBJECTS: three 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. METHODS: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed. RESULTS: home-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. CONCLUSIONS: further 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.

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.

Asymmetric Influence of Vocalic Context on Mandarin Sibilants: Evidence From ERP Studies.

In the present study, we examine the interactive effect of vowels on Mandarin fricative sibilants using a passive oddball paradigm to determine whether the HEIGHT features of vowels can spread on the surface and influence preceding consonants with unspecified features. The stimuli are two pairs of Mandarin words ([sa] ∼ [ʂa] and [su] ∼ [ʂu]) contrasting in vowel HEIGHT ([LOW] vs. [HIGH]). Each word in the same pair was presented both as standard and deviant, resulting in four conditions (/standard/[deviant]: /sa/[ʂa] ∼ /ʂa/[sa] and /su/[ʂu] ∼ /ʂu/[su]). In line with the Featurally Underspecified Lexicon (FUL) model, asymmetric patterns of processing were found in the [su] ∼ [ʂu] word pair where both the MMN (mismatch negativity) and LDN (late discriminative negativity) components were more negative in /su/[ʂu] (mismatch) than in /ʂu/[su] (no mismatch), suggesting the spreading of the feature [HIGH] from the vowel [u] to [ʂ] on the surface. In the [sa] ∼ [ʂa] pair, however, symmetric negativities (for both MMN and LDN) were observed as there is no conflict between the surface feature [LOW] from [a] to [ʂ] and the underlying specified feature [LOW] of [s]. These results confirm that not all features are fully specified in the mental lexicon: features of vowels can spread on the surface and influence surrounding unspecified segments.

Mismatch negativity (MMN) as an index of asymmetric processing of consonant duration in fake Mandarin geminates.

Unlike languages where consonant duration is used contrastively to distinguish word meanings, long consonants in Mandarin Chinese only occur across morpheme boundaries as a result of concatenation and are referred to as fake geminates. To investigate whether Mandarin speakers employ duration contrast to differentiate fake Mandarin geminates and corresponding singletons as well as the underlying pattern of the processing, two auditory oddball tasks were carried out to measure the component of MMN, an index of the automatic detection of deviant stimulus. Mandarin pseudoword pairs which differ only in the duration of the medial consonant ([an1 an1] âˆ¼ [an1 nan1] vs. [an2 an2] âˆ¼ [an2 nan2]) were used as stimuli. An asymmetric pattern of brain activation was observed where the singleton deviant in the context of geminate words elicited higher MMNs than in the reversed condition. These findings are in line with earlier research suggesting that the singleton is unspecified for a moraic representation, while the geminate is specified. Mandarin speakers can employ duration contrast to distinguish fake geminates and corresponding singletons; furthermore, the processing of fake concatenated geminates in contrast to singletons is similar to that of real geminates and corresponding singletons.

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

INTRODUCTION: Warfarin 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. MATERIALS AND METHODS: 131 patients completing a course of warfarin provided blood samples over 9 days for initial genotyping, and measurement of INR and plasma warfarin enantiomer concentrations. RESULTS: S-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 (P < 0.001). Regression analysis revealed that patient age (P = 0.037) and CYP2C9 *2*2 & *2*3 genotype (P = 0.005), but not VKORC1 genotype, significantly affected the time taken for the resumption of normal coagulation (INR value declining to ≤1.5). CONCLUSIONS: The 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.

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.

Drug metabolism and ageing.

Older people are major consumers of drugs and because of this, as well as co-morbidity and age-related changes in pharmacokinetics and pharmacodynamics, are at risk of associated adverse drug reactions. While age does not alter drug absorption in a clinically significant way, and age-related changes in volume of drug distribution and protein binding are not of concern in chronic therapy, reduction in hepatic drug clearance is clinically important. Liver blood flow falls by about 35% between young adulthood and old age, and liver size by about 24-35% over the same period. First-pass metabolism of oral drugs avidly cleared by the liver and clearance of capacity-limited hepatically metabolized drugs fall in parallel with the fall in liver size, and clearance of drugs with a high hepatic extraction ratio falls in parallel with the fall in hepatic blood flow. In normal ageing, in general, activity of the cytochrome P450 enzymes is preserved, although a decline in frail older people has been noted, as well as in association with liver disease, cancer, trauma, sepsis, critical illness and renal failure. As the contribution of age, co-morbidity and concurrent drug therapy to altered drug clearance is impossible to predict in an individual older patient, it is wise to start any drug at a low dose and increase this slowly, monitoring carefully for beneficial and adverse effects.

Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin.

OBJECTIVE: Our objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. METHODS: Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R- and S-warfarin, and triglyceride concentrations. RESULTS: A total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild-type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 +/- 1.72 mg in homozygous wild-type patients to 3.63 +/- 1.78 mg for *1/*2-positive patients and 2.70 +/- 1.36 mg for *1/*3-positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P <.001), genotype (r = 0.24, P <.005), and age and genotype together (r = 0.45, P <.005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P =.02), body weight (r = 0.25, P =.005), and plasma vitamin K concentration (r = 0.18, P <.05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S-warfarin clearance (r = 0.34, P <.0001) but none on R-warfarin clearance. CONCLUSION: This study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long-term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy.

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.