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.

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

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.

Pharmacogenetics of anticoagulants used for stroke prevention in patients with atrial fibrillation.

Introduction: The inclusion of pharmacogenetics alongside clinical information in anticoagulant therapy offers the opportunity for a tailored approach to treatment according to individual patient characteristics. Areas covered: Literature was searched using PubMed database, focusing on pharmacogenetics of oral anticoagulants. Original research articles and review articles in English language were included in the literature reviewed. This article includes all information available for the genetic cause of inter-individual variability in anticoagulation response to oral anticoagulant drugs. The pharmacogenetics of VKAs and NOACs are described in detail. Expert opinion: There have been numerous studies focusing on the pharmacogenetics of VKAs, particularly warfarin. Current evidence suggests that known genetic and clinical factors explain a large proportion of the inter-individual variability in response to warfarin. Pharmacogenetic-based algorithms have been validated to determine their clinical utility with equivocal results. To date, only a limited number of mostly small studies on the pharmacogenetics of NOACs exists. The latter have highlighted genetic polymorphisms in specific genes that may affect clinical outcomes. Further evaluations of these polymorphisms are needed before firm conclusions can be drawn about the significance of pharmacogenetics on NOAC therapy.

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.

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.

Warfarin Dose Model for the Prediction of Stable Maintenance Dose in Indian Patients.

The main aim of this study was to screen various genetic and nongenetic factors that are known to alter warfarin response and to generate a model to predict stable warfarin maintenance dose for Indian patients. The study comprised of 300 warfarin-treated patients. Followed by extensive literature review, 10 single-nucleotide polymorphisms, that is, VKORC1-1639 G>A (rs9923231), CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), FVII R353Q (rs6046), GGCX 12970 C>G (rs11676382), CALU c.*4A>G (rs1043550), EPHX1 c.337T>C (rs1051740), GGCX: c.214+597G>A (rs12714145), GGCX: 8016G>A (rs699664), and CYP4F2 V433M (rs2108622), and 5 nongenetic factors, that is, age, gender, smoking, alcoholism, and diet, were selected to find their association with warfarin response. The univariate analysis was carried out for 15 variables (10 genetic and 5 nongenetic). Five variables, that is, VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3, age, and diet, were found to be significantly associated with warfarin response in univariate analysis. These 5 variables were entered in stepwise and multiple regression analysis to generate a prediction model for stable warfarin maintenance dose. The generated model scored R2 of .67, which indicates that this model can explain 67% of warfarin dose variability. The generated model will help in prescribing more accurate warfarin maintenance dosing in Indian patients and will also help in minimizing warfarin-induced adverse drug reactions and a better quality of life in these patients.

Genetic and Clinical Factors Are Associated With Statin-Related Myotoxicity of Moderate Severity: A Case-Control Study.

We evaluated the contribution of patient-specific clinical and genetic factors to statin-related muscle toxicity (SRM) without a significant creatine kinase elevation (125 cases related to simvastatin or atorvastatin and 481 controls). The association between 12 single nucleotide polymorphisms (SNPs) in nine candidate genes and clinical factors with SRM was evaluated. Of the 12 SNPs genotyped, only rs4149056 in SLCO1B1 was associated with SRM in univariate analysis (with any statin, odd ratio (OR) = 1.73, 95% confidence interval (CI) = 1.14-2.62, P = 0.010) and this association was influenced by sex (P = 0.006) and BMI (P = 0.02). In multivariate and binary logistic regression analyses, SLCO1B1 rs4149056 genotype (OR = 1.66, 95% CI: 1.08-2.54, P = 0.014) and sex (OR = 1.72, 95% CI = 1.15-2.59, P = 0.006) were independently associated with muscle toxicity related to statin treatment. Patient-specific genetic and clinical factors associated with increased systemic exposure to statins are implicated in the full spectrum of SRM, including myalgia in addition to severe myopathy.

Alcohol and other substance use among medical and law students at a UK university: a cross-sectional questionnaire survey.

PURPOSE OF THE STUDY: To examine the use of alcohol and other substances among medical and law students at a UK university. STUDY DESIGN: Anonymous cross-sectional questionnaire survey of first, second and final year medical and law students at a single UK university. RESULTS: 1242 of 1577 (78.8%) eligible students completed the questionnaire. Over half of first and second year medical students (first year 53.1%, second year 59.7%, final year 35.9%) had an Alcohol Use Disorders Identification Test (AUDIT) score suggestive of an alcohol use disorder (AUDIT≥8), compared with over two-thirds of first and second year law students (first year 67.2%, second year 69.5%, final year 47.3%). Approximately one-quarter of medical students (first year 26.4%, second year 28.4%, final year 23.7%) and over one-third of first and second year law students (first year 39.1%, second year 42.4%, final year 18.9%) reported other substance use within the past year. Over one-third of medical students (first year 34.4%, second year 35.6%, final year 46.3%) and approximately half or more of law students (first year 47.2%, second year 52.7%, final year 59.5%) had a Hospital Anxiety and Depression Scale anxiety score suggestive of a possible anxiety disorder. CONCLUSIONS: Study participants had high levels of substance misuse and anxiety. Some students' fitness to practice may be impaired as a result of their substance misuse or symptoms of psychological distress. Further efforts are needed to reduce substance misuse and to improve the mental well-being of students.

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.

Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease.

INTRODUCTION: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin. Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability. Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.

Association between CYP4F2 genotype and circulating plasma vitamin K concentration in children on chronic warfarin therapy: Possible long-term implications for bone development and vascular health.

Vitamin K is essential, for the activation of clotting proteins, as well as the biosynthesis of osteocalcin in bones and the activation of matrix-Gla protein needed in maintaining vasculature health. Cytochrome p450 4F2 (CYP4F2) enzyme is involved in vitamin K catabolism. Genetic polymorphism in CYP4F2 is thus likely to affect vitamin K systemic availability. We show that children on chronic warfarin therapy have low levels of vitamin K and vitamin K levels are linked to CYP4F2 genotype. Long-term low levels of vitamin K, influenced by CYP4F2 genotype, might affect bone development and vascular health in children on chronic warfarin therapy.

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.

A multi-factorial analysis of response to warfarin in a UK prospective cohort.

BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. METHODS: A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. RESULTS: VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. CONCLUSION: Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.

Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants.

INTRODUCTION: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. MATERIALS AND METHODS: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged >18years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. RESULTS: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3months treatment period, patients experienced an improvement (p<0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p<0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. CONCLUSIONS: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.

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.

Oral anticoagulation: a critique of recent advances and controversies.

There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.

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.