Saied Ibrahim

An international multicenter randomized study of computer‐assisted oral anticoagulant dosage vs. medical staff dosage

Summary.  Background: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer‐assisted dosage with dosage by experienced medical staff at the same centers. Methods: A randomized study of dosage of two commercial computer‐assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16 000 patient‐years randomized to medical staff or computer‐assisted dosage. In total, 13 219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer‐assisted dosage. The safety and effectiveness of computer‐assisted dosage were compared with those of medical staff dosage. Results: In total, 13 052 patients were recruited (18 617 patient‐years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193 424 with computer‐assisted dosage. The number of clinical events with computer‐assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). Conclusions: The safety and effectiveness of computer‐assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer‐assisted dosage programs need to be established.

A national field study of quality assessment of CoaguChek point-of-care testing prothrombin time monitors.

A system for quality assessment (QA) of the CoaguChek (Roche Diagnostics, Mannheim, Germany) point-of-care testing prothrombin time monitor has been developed by the European Concerted Action on Anticoagulation. Hitherto there has not been an adequate rapid method for CoaguChek QA. Sets of 5 certified international normalized ratio (INR) plasma samples were tested on 539 CoaguChek monitors by experienced staff at 9 Netherlands Thrombosis Centers and results compared with certified INR. A 15% or more deviation has been classified as significant deviation. Overall mean and certified INR values were similar, but 20.3% of participants showed a 15% or more deviation from the certified INR on at least 1 of the 5 QA plasma samples. Statistically significant differences in results with different lots of CoaguChek test strips were found. There is need for large scale QA of CoaguChek monitors. The importance of the 5 CoaguChek certified INR QA plasma samples being tested on a single occasion is demonstrated.

The clinical evaluation of International Normalized Ratio variability and control in conventional oral anticoagulant administration by use of the variance growth rate

The time in target International Normalized Ratio (INR) range (TIR) is used to assess the control and intensity of oral anticoagulation, but it does not measure variation in the INR.

The cost-effectiveness of computer-assisted anticoagulant dosage: results from the European Action on Anticoagulation (EAA) multicentre study

Background: Increased demand for oral anticoagulation has resulted in wider adoption of computer‐assisted dosing in anticoagulant clinics. An economic evaluation has been performed to investigate the cost‐effectiveness of computer‐assisted dosing in comparison with manual dosing in patients on oral anticoagulant therapy. Methods: A trial‐based cost‐effectiveness analysis was conducted as part of the EAA randomized study of computer‐assisted dosage vs. manual dosing. The 4.5‐year multinational trial was conducted in 32 centres with 13 219 anticoagulation patients randomized to manual or computer‐assisted dosage. The main outcome measures were total health care costs, clinical event rates and cost‐saving per clinical event prevented by computer dosing compared with manual dosing. Results: Mean dosing costs per patient were lower (difference: €47) for computer‐assisted dosing, but with little difference in clinical event costs. Total overall costs were €51 lower in the computer‐assisted dosing arm. There were a larger number of clinical events in the manual dosing arm. The overall difference between trial arms was not significant (difference in clinical events, −0.003; 95% CI, −0.010–0.004) but there was a significant reduction in events with DVT/PE, suggesting computer‐assisted dosage with the two study programs (dawn ac or parma 5) was at least as effective clinically as manual dosage. The cost‐effectiveness analysis indicated that computer‐assisted dosing is less costly than manual dosing. Conclusions: Results indicate that computer‐assisted dosage with the two programs (dawn ac and parma 5) is cheaper than manual dosage and is at least as effective clinically, indicating that investment in this technology represents value for money.

A multicentre randomised clinical endpoint study of PARMA 5 computer-assisted oral anticoagulant dosage

To meet growing demand for oral anticoagulation worldwide there has been increased dependence on computer‐assistance in dosage although the safety and effectiveness of any of the individual computer‐assisted dosage programs has not previously been established. This randomised multicentre clinical end‐point study assessed a new version of the parma 5 program. It compared parma 5 safety and effectiveness with manual dosage by experienced medical staff at 19 centres with a known interest in oral anticoagulation. Target recruitment was 8000 patient‐years, randomised to medical staff or parma‐5 assisted dosage. Safety and effectiveness of the parma 5 program was compared with manual dosage. A total of 10 421 patients were recruited (15 369 patient‐years) in the 5‐year study. International normalised ratio (INR) tests numbered 167 791 with manual and 160 078 with parma 5 dosage. With parma 5 there was overall a non‐significant reduction in clinical events but in the 2542 patients with deep vein thrombosis/pulmonary embolism, clinical events were significantly reduced (P = 0·005). Success in achieving ‘time in target INR range’ was also significantly greater with parma 5 compared with the dosage by experienced medical staff. This study demonstrated the safety and effectiveness of parma 5‐assisted dosage.

Suicide in children and young people in England: a consecutive case series

BACKGROUND There is concern about the mental health of children and young people and a possible rise in suicidal behaviour in this group. We have done a comprehensive national multi-agency study of suicide in under 20s in England. We aimed to establish how frequently suicide is preceded by child-specific and young person-specific suicide risk factors, as well as all-age factors, and to identify contact with health-care and social-care services and justice agencies. METHODS This study is a descriptive examination of suicide in a national consecutive sample of children and young people younger than 20 years who died by suicide in England between Jan 1, 2014, and April 30, 2015. We obtained general population mortality data from the Office for National Statistics (ONS). We collected information about antecedents considered to be relevant to suicide (eg, abuse, bullying, bereavement, academic pressures, self-harm, and physical health) from a range of investigations and inquiries, including coroner inquest hearings, child death investigations, criminal justice system reports, and the National Health Service, including data on people in contact with mental health services in the 12 months before their death. FINDINGS 145 suicides in people younger than 20 years were notified to us during the study period, of which we were able to obtain report data about antecedents for 130 (90%). The number of suicides rose sharply during the late teens with 79 deaths by suicide in people aged 18-19 years compared with 66 in people younger than 18 years. 102 (70%) deaths were in males. 92 (63%) deaths were by hanging. Various antecedents were reported among the individuals for whom we had report data, including academic (especially exam) pressures (35 [27%] individuals), bullying (28 [22%]), bereavement (36 [28%]), suicide in family or friends (17 [13%]), physical health conditions (47 [36%]), family problems (44 [34%]), social isolation or withdrawal (33 [25%]), child abuse or neglect (20 [15%]), excessive drinking (34 [26%]), and illicit drug use (38 [29%]). Suicide-related internet use was recorded in 30 (23%) cases. In the week before death 13 (10%) individuals had self-harmed and 35 (27%) had expressed suicidal ideas. 56 (43%) individuals had no known contact with health-care and social-care services or justice agencies. INTERPRETATION Improved services for self-harm and mental health are crucial to suicide prevention, but the wide range of antecedents emphasises the roles of schools, primary care, social services, and the youth justice system. FUNDING The Healthcare Quality Improvement Partnership.

Mental health service changes, organisational factors, and patient suicide in England in 1997–2012: a before-and-after study

BACKGROUND Research into which aspects of service provision in mental health are most effective in preventing suicide is sparse. We examined the association between service changes, organisational factors, and suicide rates in a national sample. METHODS We did a before-and-after analysis of service delivery data and an ecological analysis of organisational characteristics, in relation to suicide rates, in providers of mental health care in England. We also investigated whether the effect of service changes varied according to markers of organisational functioning. FINDINGS Overall, 19 248 individuals who died by suicide within 12 months of contact with mental health services were included (1997-2012). Various service changes related to ward safety, improved community services, staff training, and implementation of policy and guidance were associated with a lower suicide rate after the introduction of these changes (incidence rate ratios ranged from 0·71 to 0·79, p<0·0001). Some wider organisational factors, such as non-medical staff turnover (Spearmans r=0·34, p=0·01) and incident reporting (0·46, 0·0004), were also related to suicide rates but others, such as staff sickness (-0·12, 0·37) and patient satisfaction (-0·06, 0·64), were not. Service changes had more effect in organisations that had low rates of staff turnover but high rates of overall event reporting. INTERPRETATION Aspects of mental health service provision might have an effect on suicide rates in clinical populations but the wider organisational context in which service changes are made are likely to be important too. System-wide change implemented across the patient care pathway could be a key strategy for improving patient safety in mental health care. FUNDING The Healthcare Quality Improvement Partnership commissions the Mental Health Clinical Outcome Review Programme, National Confidential Inquiry into Suicide and Homicide by People with Mental Illness, on behalf of NHS England, NHS Wales, the Scottish Government Health and Social Care Directorate, the Northern Ireland Department of Health, Social Services and Public Safety, and the States of Jersey and Guernsey.

Comparison of local International Sensitivity Index calibration and ‘Direct INR’ methods in correction of locally reported International Normalized Ratios: an international study

Summary.  Background: It is no longer feasible to check local International Normalized Ratios (INR) by the World Health Organization International Sensitivity Index (ISI) calibrations because the necessary manual prothrombin time technique required has generally been discarded. Objectives: An international collaborative study at 77 centers has compared local INR correction using the two alternative methods recommended in the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis guidelines: local ISI calibration and ‘Direct INR’. Methods: Success of INR correction by local ISI calibration and with Direct INR was assessed with a set of 27 certified lyophilized plasmas (20 from patients on warfarin and seven from normals). Results: At 49 centers using human thromboplastins, 3.0% initial average local INR deviation from certified INR was reduced by local ISI calibration to 0.7%, and at 25 centers using rabbit reagents, from 15.9% to 7.5%. With a minority of commercial thromboplastins, mainly ‘combined’ rabbit reagents, INR correction was not achieved by local ISI calibration. However, when rabbit combined reagents were excluded the overall mean INR deviation after correction was reduced further to 3.9%. In contrast, with Direct INR, mean deviation using human thromboplastins increased from 3.0% to 6.6%, but there was some reduction with rabbit reagents from 15.9% to 10% (12.3% with combined reagents excluded). Conclusions: Local ISI calibration gave INR correction for the majority of PT systems but failed at the small number using combined rabbit reagents suggesting a need for a combined reference thromboplastin. Direct INR correction was disappointing but better than local ISI calibration with combined rabbit reagents. Interlaboratory variability was improved by both procedures with human reagents only.

The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers--two independent studies.

Summary.  Background: The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP). Methods: The value of a new simpler procedure to derive international normalized ratio (INR), the PT/INR Line, based on only five European Concerted Action on Anticoagulation (ECAA) calibrant plasmas certified by experienced centres has been assessed in two independent exercises using a range of commercial thromboplastins and coagulometers. INRs were compared with manual certified values with thromboplastin IRP from expert centres and in the second study also with INRs from local ISI calibrations. Results: In the first study with the PT/INR Line, 8.7% deviation from certified INRs was reduced to 1.1% with human reagents, and from 7.0% to 2.6% with rabbit reagents. In the second study, deviation was reduced from 11.2% to 0.4% with human reagents by both local ISI calibration and the PT/INR Line. With rabbit reagents, 10.4% deviation was reduced to 1.1% with both procedures; 4.9% deviation was reduced to 0.5% with bovine/combined reagents with local ISI calibrations and to 2.9% with the PT/INR Line. Mean INR dispersion was reduced with all thromboplastins and automated systems using the PT/INR Line. Conclusions: The procedure using the PT/INR Line provides reliable INR derivation without the need for WHO ISI calibration across the range of locally used commercial thromboplastins and automated PT systems included in two independent international studies.

External quality assessment (EQA) for CoaguChek monitors.

Anticoagulant control facilities are being overwhelmed by requests for monitoring and large numbers of patients are not therefore receiving treatment. Procedures designed for point-of-care testing have therefore been developed, the most popular being the CoaguChek. The need for external quality assessment (EQA) of monitors used by patients in self-management has been stressed in a European Commission (EC) Directive. It would not however be feasible for all CoaguChek monitors to be enrolled in national or regional EQA schemes which take time to organise and analyse. The European Concerted Action on Anticoagulation (ECAA) has therefore evolved a simpler system. Its value has been assessed in collaboration with the European Concerted Action on Thrombosis (ECAT). 523 monitors were tested at nine clinics which asked patients to bring their CoaguChek instruments to be assessed with the ECAA/ECAT procedure based on a set of 5 plasma samples with certified international normalised ratios (INR). 15% or more deviation from the certified INR on a single certified plasma sample from the set was defined by the ECAA as the limit of acceptable performance. One hundred and six (20.3%) of the monitors tested showed significant deviation and higher than average incidence of significant INR deviations reported with one specific numbered lot of test strips. Recent ECAA/ECAT, Danish and Italian studies report regular EQA of CoaguChek monitors is essential. There is general agreement that this should be performed at reasonably frequent intervals, at six months or whenever there is a change of the manufacturers test strips.