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

ABSTRACT: 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.

SUBMITTER: Bourgeois S

PROVIDER: S-EPMC4702374 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundPoor anticoagulation management of warfarin may lead to patient admission, prolonged hospital stays, and even death due to anticoagulation-related adverse events. Traditional non-web-based outpatient clinics struggle to provide ideal anticoagulation management services for patients, and there is a need to explore a safer, more effective, and more convenient mode of warfarin management.ObjectiveThis study aimed to compare differences in the quality of anticoagulation management and clinical adverse events between a web-based management model (via a smartphone app) and the conventional non-web-based outpatient management model.MethodsThis study is a prospective cohort research that includes multiple national centers. Patients meeting the nadir criteria were split into a web-based management group using the Alfalfa app or a non-web-based management group with traditional outpatient management, and they were then monitored for a 6-month follow-up period to collect coagulation test results and clinical events. The effectiveness and safety of the 2 management models were assessed by the following indicators: time in therapeutic range (TTR), bleeding events, thromboembolic events, all-cause mortality events, cumulative event rates, and the distribution of the international normalized ratio (INR).ResultsThis national multicenter cohort study enrolled 522 patients between June 2019 and May 2021, with 519 (99%) patients reaching the follow-up end point, including 260 (50%) in the non-web-based management group and 259 (50%) in the web-based management group. There were no observable differences in baseline characteristics between the 2 patient groups. The web-based management group had a significantly higher TTR than the non-web-based management group (82.4% vs 71.6%, P<.001), and a higher proportion of patients received effective anticoagulation management (81.2% vs 63.5%, P<.001). The incidence of minor bleeding events in the non-web-based management group was significantly higher than that in the web-based management group (12.1% vs 6.6%, P=.048). Between the 2 groups, there was no statistically significant difference in the incidence of severe bleeding and thromboembolic and all-cause death events. In addition, compared with the non-web-based management group, the web-based management group had a lower proportion of INR in the extreme subtreatment range (17.6% vs 21.3%) and severe supertreatment range (0% vs 0.8%) and a higher proportion in the treatment range (50.4% vs 43.1%), with statistical significance.ConclusionsCompared with traditional non-web-based outpatient management, web-based management via the Alfalfa app may be more beneficial because it can enhance patient anticoagulation management quality, lower the frequency of small bleeding events, and improve INR distribution.

Project description:BackgroundComponents of social connection are associated with mortality, but research examining their independent and combined effects in the same dataset is lacking. This study aimed to examine the independent and combined associations between functional and structural components of social connection and mortality.MethodsAnalysis of 458,146 participants with full data from the UK Biobank cohort linked to mortality registers. Social connection was assessed using two functional (frequency of ability to confide in someone close and often feeling lonely) and three structural (frequency of friends/family visits, weekly group activities, and living alone) component measures. Cox proportional hazard models were used to examine the associations with all-cause and cardiovascular disease (CVD) mortality.ResultsOver a median of 12.6 years (IQR 11.9-13.3) follow-up, 33,135 (7.2%) participants died, including 5112 (1.1%) CVD deaths. All social connection measures were independently associated with both outcomes. Friends/family visit frequencies < monthly were associated with a higher risk of mortality indicating a threshold effect. There were interactions between living alone and friends/family visits and between living alone and weekly group activity. For example, compared with daily friends/family visits-not living alone, there was higher all-cause mortality for daily visits-living alone (HR 1.19 [95% CI 1.12-1.26]), for never having visits-not living alone (1.33 [1.22-1.46]), and for never having visits-living alone (1.77 [1.61-1.95]). Never having friends/family visits whilst living alone potentially counteracted benefits from other components as mortality risks were highest for those reporting both never having visits and living alone regardless of weekly group activity or functional components. When all measures were combined into overall functional and structural components, there was an interaction between components: compared with participants defined as not isolated by both components, those considered isolated by both components had higher CVD mortality (HR 1.63 [1.51-1.76]) than each component alone (functional isolation 1.17 [1.06-1.29]; structural isolation 1.27 [1.18-1.36]).ConclusionsThis work suggests (1) a potential threshold effect for friends/family visits, (2) that those who live alone with additional concurrent markers of structural isolation may represent a high-risk population, (3) that beneficial associations for some types of social connection might not be felt when other types of social connection are absent, and (4) considering both functional and structural components of social connection may help to identify the most isolated in society.

Project description:BackgroundSurvivors of critical illness have significant psychopathological comorbidity. The treatments offered by primary health care professionals to affected patients are unstudied.AimTo report the psychological interventions after GPs received notification of patients who showed severe symptoms of anxiety, depression or Post-Traumatic Stress Disorder.MethodsDesign: Multi-centre prospective cohort sub-study of the ICON study.SettingNHS primary care in the United Kingdom.ParticipantsAdult patients, November 2006-October 2010 who had received at least 24 h of intensive care, where the general practitioner recorded notification that the patient had reported severe symptoms or caseness using the Hospital Anxiety and Depression Scale (HADS) or the Post-Traumatic Stress Disorder Check List-Civilian (PCL-C).InterventionsWe notified general practitioners (GPs) by post if a patient reported severe symptoms or caseness and sent a postal questionnaire to determine interventions after notification.Main outcome measurePrimary or secondary healthcare interventions instigated by general practitioners following notification of a patient's caseness.ResultsOf the 11,726 patients, sent questionnaire packs containing HADS and PCL-C, 4361 (37%) responded. A notification of severe symptoms was sent to their GP in 25% (1112) of cases. Of notified GPs, 65% (725) responded to our postal questionnaire. Of these 37% (266) had no record of receipt of the original notification. Of the 459 patients where GPs had record of notification (the study group for this analysis), 21% (98) had pre-existing psychopathology. Of those without a pre-existing diagnosis 45% (162) received further psychological assessment or treatment. GP screening or follow-up alone occurred in 18% (64) whilst 27% (98) were referred to mental health services or received drug therapy following notification.ConclusionsPostal questionnaire identifies a burden of psychopathology in survivors of critical illness that have otherwise gone undiagnosed following discharge from an intensive care unit (ICU). After being alerted to the presence of psychological symptoms, GPs instigate treatment in 27% and augmented surveillance in 18% of cases.Trial registrationISRCTN69112866 (assigned 02/05/2006).

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

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