International Normalized Ratio Determination Research Articles

Effectiveness of a self-management program for anticoagulated patients to improve their knowledge about treatment and time in therapeutic range.

Oral anticoagulation self-control programs have demonstrated efficiency and cost-effectiveness over recent years. This study aimed to evaluate the effectiveness of a training intervention focused on patients with antivitamin K anticoagulants included in a self-care program. For this, we made a quasi-experimental study, pretest and post-test, using a validated questionnaire with 2 measures, before and after an educational intervention about oral anticoagulation focused on patients that will initiate the self-control program in consultation. To check the patient's adherence and coagulation level, we evaluated the Rosendaal time in therapeutic rank, both before and after the intervention. One hundred fifty patients were included since the start of the self-monitoring program in our center in 2016. The mean age was 49 years (standard deviation [SD] = 17.24). The distribution by gender was 76 women and 69 men (52.4%-47.6%). The mean score for the first test was 14.61 (SD = 3.26) and the mean score for the second test was 17.01 (SD = 2.14) (P <.001). We also measured Rosendaal time in therapeutic rank, a parameter that indicates stabilization in international normalized ratio determinations and quality of the anticoagulation management. Values before and after interventions were also statistically significant (67.46 vs 70.53, P <.001). Patients' knowledge improved after the training session, with statistical significance. Despite intentional sampling, the population was homogeneous. Scoring data dispersion in the second test was significantly lower than in the first one. Time on therapeutic rank values was better after the training. We intend to adapt its content to the rest of anticoagulated patients to enhance and improve their follow-up.

Cost-Utility and Budget Impact Analysis of Implementing Anticoagulation Clinics and Point-of-Care Monitoring Devices in Anticoagulated Patients in Argentina.

BackgroundWorldwide, 1 % of the population receives anticoagulation therapy, with prevalence higher in older adults. Difficulties in the adequate management of these patients have led to the development of strategies focused on achieving therapeutic control and reducing adverse events with efficient use of resources.ObjectiveTo estimate the cost utility and budget impact on the Argentinean health system of implementation of anticoagulation clinics (ACs) (with and without use of point-of-care [POC] CoaguChek® devices [Roche Diagnostics International Ltd]) compared with the traditional laboratory method (non-AC settings) for the management of anticoagulated patients.MethodsFor the cost-utility analysis, a cohort-based state transition model was designed to compare costs and health outcomes of implementing ACs for outpatient management of anticoagulated patients. The budget impact analysis used an analytical model to estimate the differential costs of implementing an AC and the expected adverse events avoided, and the differential costs of an international normalized ratio (INR) determination using a POC device rather than a conventional laboratory.ResultsWe calculated the study outcomes for a cohort of 1000 patients. Considering a 5 % discount rate, the use of ACs generated 13.9 additional quality-adjusted life-years (0.014 per patient) and 12.5 additional life-years (0.013 per patient). Incremental cost-effectiveness ratios of AC implementation with and without the use of POC devices compared with the scenario without ACs were dominant in both cases. In the probabilistic sensitivity analysis, nearly all simulated results were cost effective (i.e., below the 1 or 3 gross domestic product per capita thresholds). Budget impact analysis results showed AC implementation generated savings from the first year of implementation, with savings of AR $265,325 by year 5. The addition of POC devices in the ACs also generated savings as early as the first year of implementation, with savings of AR $488,072 by year 5 (AR $488 per patient).ConclusionsAnticoagulation clinics are estimated to be cost effective and generate notable savings in the treatment of patients on long-term oral anticoagulant therapy when compared with non-AC settings. These savings are considerably higher when POC devices are added as part of the patient management, due to lower laboratory technician costs per INR determination.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00352-4.

Variables affecting the quality of anticoagulation in atrial fibrillation patients newly initiating vitamin K antagonists: insights from the national and multicentre SULTAN registry.

Vitamin K antagonists (VKAs) are effective drugs reducing the risk for stroke in atrial fibrillation (AF), but the benefits derived from such therapy depend on the international normalized ratio (INR) maintenance in a narrow therapeutic range. Here, we aimed to determine independent variables driving poor anticoagulation control [defined as a time in therapeutic range (TTR) <65%] in a 'real world' national cohort of AF patients. The SULTAN registry is a multicentre, prospective study, involving patients with non-valvular AF from 72 cardiology units expert in AF in Spain. At inclusion, all patients naïve for oral anticoagulation were started with VKAs for the first time. For the analysis, the first month of anticoagulation and those patients with <3 INR determinations were disregarded. Patients were followed up during 1 year. A total of 870 patients (53.9% male, the mean age of 73.6 ± 9.2 years, mean CHA2DS2-VASc and HAS-BLED of 3.3 ± 1.5 and 1.4 ± 0.9, respectively) were included in the full analysis set. In overall, 7889 INR determinations were available. At 1-year, the mean TTR was 63.1 ± 22.1% and 49.2% patients had a TTR < 65%. Multivariate Cox regression analysis showed that coronary artery disease [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.14-2.87; P = 0.012] and amiodarone use (OR 1.54, 95% CI 1.01-2.34; P = 0.046) were independently associated with poor quality of anticoagulation (TTR <65%). This study demonstrated that the quality of anticoagulation in AF patients newly starting VKAs is sub-optimal. Previous coronary artery disease and concomitant use of amiodarone were identified as independent variables affecting the poor quality of VKA therapy during the first year.

Effects of a Feedback-Demanding Stroke Clock on Acute Stroke Management: A Randomized Study.

This randomized study aimed to evaluate whether the use of a stroke clock demanding active feedback from the stroke physician accelerates acute stroke management. For this randomized controlled study, a large-display alarm clock was installed in the computed tomography room, where admission, diagnostic work-up, and intravenous thrombolysis occurred. Alarms were set at the following target times after admission: (1) 15 minutes (neurological examination completed); (2) 25 minutes (computed tomography scanning and international normalized ratio determination by point-of-care laboratory completed); and (3) 30 minutes (intravenous thrombolysis started). The responsible stroke physician had to actively provide feedback by pressing a buzzer button. The alarm could be avoided by pressing the button before time out. Times to therapy decision (primary end point, defined as the end of all diagnostic work-up required for decision for or against recanalizing treatment), neurological examination, imaging, point-of-care laboratory, needle, and groin puncture were assessed by a neutral observer. Functional outcome (modified Rankin Scale) was assessed at day 90. Of 107 participants, 51 stroke clock patients exhibited better stroke-management metrics than 56 control patients. Times from door to (1) end of all indicated diagnostic work-up (treatment decision time; 16.73 versus 26.00 minutes, P<0.001), (2) end of neurological examination (7.28 versus 10.00 minutes, P<0.001), (3) end of computed tomography (11.17 versus 14.00 minutes, P=0.002), (4) end of computed tomography angiography (14.00 versus 17.17 minutes, P=0.001), (5) end of point-of-care laboratory testing (12.14 versus 20.00 minutes, P<0.001), and (6) needle times (18.83 versus 47.00 minutes, P=0.016) were improved. In contrast, door-to-groin puncture times and functional outcomes at day 90 were not significantly different. This study showed that the use of a stroke clock demanding active feedback significantly improves acute stroke-management metrics and, thus, represents a potential low-cost strategy for streamlining time-sensitive stroke treatment.

Assignment of international normalized ratio to frozen and freeze-dried pooled plasmas.

Objectives Frozen and freeze-dried plasmas may be used for local prothrombin time system calibration, for direct international normalized ratio (INR) determination, and for quality assessment. The purpose of the present study was to evaluate the usefulness of INRs assigned with various types of thromboplastins to frozen and freeze-dried pooled plasmas obtained from patients treated with vitamin K antagonists. Methods INRs were calculated according to the international sensitivity index (ISI) model using various thromboplastins and instruments, i.e. International Standards for thromboplastin as well as six commercial reagents prepared from rabbit and bovine brain, and recombinant human tissue factor. The uncertainty of the INRs was assessed using the standard deviations of clotting times and ISI values. Commutability of the plasmas was assessed according to the approved Clinical and Laboratory Standards Institute (CLSI) Guideline EP30-A. Validation of a set of six frozen plasma pools for direct INR determination was performed according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC/ISTH) guidelines. Results For all frozen and freeze-dried plasmas, the INRs calculated with bovine thromboplastin Thrombotest were lower than the INRs assigned with other thromboplastins. With a few exceptions, the frozen and freeze-dried pooled plasmas were commutable. When the set of six frozen plasma pools was used for local calibration, the analytical bias of the INR was less than ±10% for all commercial reagents except Thrombotest. Conclusions Processing of fresh plasmas to prepare pooled frozen plasmas and freeze-dried plasmas may lead to different INR assignments depending on the thromboplastin used. Despite minor INR differences, a set of six frozen plasma pools could be used for local calibration by direct INR determination.

Group-based Trajectory Models to Assess Quality of INR Control and Its Association With Clinical Outcomes.

The Time in Therapeutic Range (TTR) is the gold-standard measure used to assess the quality of oral anticoagulation with vitamin K antagonists. However, TTR is a static measure, and International Normalized Ratio (INR) control is a dynamic process. Group-based Trajectory Models (GBTM) can address this dynamic nature by classifying patients into different trajectories of INR control over time. The objective of this study was to assess the quality of INR control in a population-based cohort of new users of vitamin K antagonist with a diagnosis of atrial fibrillation using GBTM. We classified patients into different trajectories according to their propensity for being adequately anticoagulated over their first year of treatment using GBTM, and we evaluated the association between trajectories and relevant clinical outcomes over the following year. We included 8024 patients in the cohort who fulfilled the inclusion criteria; the mean number of INR determinations over the first year of treatment was 13.9. We identified 4 differential trajectories of INR control: Optimal (9.7% of patients, TTR: 83.8%), Improving (27.4% of patients, TTR: 61.2%), Worsening (28%; TTR: 69.1%), and Poor control (34.9%; TTR: 41.5%). In adjusted analysis, Poor and Worsening control patients had a higher risk of death than Optimal control patients (hazard ratio: 1.79; IC 95%, 1.36-2.36 and hazard ratio: 1.36; IC 95%, 1.02-1.81, respectively). Differences in other outcomes did not achieve statistical significance, except for a reduced risk of transient ischemic attack in the Improving Control group. GBTM may contribute to a better understanding and assessment of the quality of oral anticoagulation and may be used in addition to traditional, well-established measures such as TTR.

ICUSI questionnaire validation. Quality of anticoagulation in patients with atrial fibrillation treated with vitamin K antagonists

Introduction and objectivesVitamin K antagonists (VKAs) are still widely used for stroke prevention in atrial fibrillation. However, the access to international normalised ratio (INR) determinations is sometimes difficult and the time in therapeutic range (TTR) is not always available. The aim of this study was to design and validate a simple and easy-to-use questionnaire that enables the identification of atrial fibrillation patients with poor quality of anticoagulation. MethodsThis is a national, multi-centre, observational, and cross-sectional study including consecutive non-valvular atrial fibrillation patients receiving VKA therapy and followed up at cardiology clinics. At inclusion, INR determinations during the last 6 months were analysed to determine the TTR and the ICUSI questionnaire was completed. A TTR < 65% was considered suboptimal. ResultsA total of 813 patients (55% men, 75±9 years old) were available for the analyses. The mean TTR was 62.2%±20.3% and 427 (52.5%) patients had a TTR < 65%. The final version of the ICUSI questionnaire included 4 questions and the mean ICUSI score was 1.19±1.17. The predictive ability of the ICUSI questionnaire for predicting TTR < 65% was moderate (c-index, 0.707; 95%CI, 0.670–0.740; P<.001). An ICUSI score of 1 showed a sensitivity of 80.8% and a specificity of 45.6%, whereas an ICUSI score of 2 showed a sensitivity of 43.2% and a specificity of 88.1%. ConclusionsThe ICUSI questionnaire has shown a good predictive performance for the identification of poor TTR in the absence of full access to the INR determinations in atrial fibrillation patients under VKA therapy.

Quality of INR control and switching to non-Vitamin K oral anticoagulants between women and men with atrial fibrillation treated with Vitamin K Antagonists in Spain. A population-based, real-world study.

BackgroundWorldwide, there is growing evidence that quality of international normalized ratio (INR) control in atrial fibrillation patients treated with Vitamin K Antagonists (VKA) is suboptimal. However, sex disparities in population-based real-world settings have been scarcely studied, as well as patterns of switching to second-line Non-VKA oral anticoagulants (NOAC). We aimed to assess the quality of INR control in atrial fibrillation patients treated with VKA in the region of Valencia, Spain, for the whole population and differencing by sex, and to identify factors associated with poor control. We also quantified switching to Non-VKA oral anticoagulants (NOAC) and we identified factors associated to switching.MethodsThis is a cross-sectional, population-based study. Information was obtained through linking different regional electronic databases. Outcome measures were Time in Therapeutic Range (TTR) and percentage of INR determinations in range (PINRR) in 2015, and percentage of switching to NOAC in 2016, for the whole population and stratified by sex.ResultsWe included 22,629 patients, 50.4% were women. Mean TTR was 62.3% for women and 63.7% for men, and PINNR was 58.3% for women and 60.1% for men (p<0.001). Considering the TTR<65% threshold, 53% of women and 49.3% of men had poor anticoagulation control (p<0.001). Women, long-term users antiplatelet users, and patients with comorbidities, visits to Emergency Department and use of alcohol were more likely to present poor INR control. 5.4% of poorly controlled patients during 2015 switched to a NOAC throughout 2016, with no sex differences.ConclusionThe quality of INR control of all AF patients treated with VKA in 2015 in our Southern European region was suboptimal, and women were at a higher risk of poor INR control. This reflects sex disparities in care, and programs for improving the quality of oral anticoagulation should incorporate the gender perspective. Clinical inertia may be lying behind the observed low rates of switching in patient with poor INR control.

Circannual variations in the international normalized ratio (INR) among mechanical heart valve surgery patients on life-long warfarin

The aim of our study was to explore if there exists a circannual rhythm in INR as fluctuations in anti-coagulation can have serious consequences in patients with mechanical heart valve prosthesis. This is a retrospective study performed in patients with stable INR value for at least 30 days post heart valve surgery in the period 2015–2016 attending a nurse-managed, cardiologist-supervised anti-coagulation clinic at King Abdul Aziz Cardiac Center.we determined average seasonal INR values for each patient, separately for aortic and mitral valve replacement patients. Data were analyzed using JMP Version 7.1, p < 0.05 considered significant. Results are expressed as mean ± SEM, differences between means were analyzed using Wilcoxon-rank sums test and chi-square as appropriate. Seasonal changes in INR were analyzed using analysis of variance of repeated measures (MANOVA), adjusting for potential confounders. Data Collected for 397 patients (mean age 50 ± 0.7 years, 56% male) with a total of 6,220 INRs; 4149 in the high target (2.5–3.5) and 2021 in the low target (2–3) patients. There was no significant difference in the number of INR determinations performed across seasons. INR decreased significantly with time, from the highest value in the summer at 2.8 ± 0.07 to lowest in winter at 2.6 ± 0.02 (p < 0.0001), irrespective of the target INR (p = 0.36). There was no significant interaction between time-related changes in INR and age, gender, INR target, renal impairment, concomitant anti-platelet treatment except for smoking, which showed a significant interaction with INR variation over time (p < 0.001). To the best of our knowledge. This is the first study in the Middle-East extending European and North-American data on circannual changes in INR. Our results confirm the existence of such a rhythm; however the mechanism is unknown. Our findings recognize winter as a challenging season for maintaining optimum anti-coagulation, possibly requiring higher number of outpatient visits and INR determinations, with implications for health care costs.

Satisfaction with oral anticoagulants in patients with atrial fibrillation.

BackgroundAlthough, by itself, atrial fibrillation is associated with an impairment of quality of life antithrombotic therapy may play a role.ObjectiveTo evaluate the satisfaction with anticoagulant treatment in patients with nonvalvular atrial fibrillation who attended internal medicine departments in Spain.MethodsPatients from two different cross-sectional studies were combined. To measure the satisfaction with anticoagulant treatment, the Anti-Clot-Treatment Scale (ACTS) questionnaire was completed by every patient. A multivariate analysis was performed to determine the variables associated with satisfaction of patients receiving oral anticoagulants.ResultsA total of 1,309 patients (mean age 78.5±8.4 years; 49.3% men; CHA2DS2VASC 4.9±1.5; HAS-BLED 2.0±0.9) were included in the study, of whom 902 (68.9%) were taking vitamin K antagonists (VKA) and 407 (31.1%) direct oral anticoagulants (DOACs). Overall, satisfaction with oral anticoagulation was high (ACTS Burdens scale 49.69±9.45; ACTS Benefits scale 11.35±2.61). The perceived burdens with anticoagulant treatment were lower in men, as well as in patients with no dependency, normal renal function, who were not polymedicated, or who had moderate bleeding risk. Among patients taking VKA, those subjects with a lower number of International Normalized Ratio (INR) determinations in the last 6 months or with an optimal time in the therapeutic range exhibited a lower perceived burden. Patients taking DOACs (vs VKA) showed a lower perceived burden with anticoagulation. Benefits with anti-coagulation were higher in men, younger patients, those with no dependency, or low bleeding risk. Perceived benefits were higher in patients taking DOACs (vs VKA).ConclusionSatisfaction with oral anticoagulation was high in patients with nonvalvular atrial fibrillation, who were attending internal medicine departments daily in Spain. Among patients taking VKA, those subjects with a lower number of INR determinations in the last 6 months or with an optimal time in the therapeutic range exhibited a lower perceived burden with anticoagulant therapy. Patients taking DOACs (vs VKA) showed lower perceived burdens and higher perceived benefits with anticoagulation.

Assessment of Oral Anticoagulant Use in Residents of Long-Term Care Homes: Evidence for Contemporary Suboptimal Use.

To describe the quality of warfarin use in residents of long-term care facilities and investigate potential predictors oral anticoagulant use. Retrospective chart review (August 2013 to September 2014). Thirteen long-term care (LTC) and assisted living facilities (ALF). Residents from LTC or ALF settings who ( a) received warfarin or direct-acting oral anticoagulants (DOACs) and ( b) residents with a valid indication for oral anticoagulants such as atrial fibrillation, venous thromboembolism, but were not receiving these drugs. Time in therapeutic international normalized ratio (INR) range (TTR). A total of 563 residents (70% female) with an average age of 85 years were identified. Participants had an average of 7.5 comorbidities and 9 medications. A total of 391 (69%) residents with indications for OACs were receiving such medications. Indications were atrial fibrillation (63%), venous or pulmonary embolism (16%), cardiac valves (0.4%); 26% did not have documented indications. Warfarin and DOACs were prescribed for 213 (38%) and 178 (32%) respectively, and 172 (31%) received no OACs The TTR ranged from 56%-75% (mean 63%). The frequency of INR determinations ranged from every 7 to 20 days, (mean 13 days) with no apparent relationship between frequency of testing and TTR. The TTR was higher (63.8%) than literature average (50%), but remains suboptimal given expected benefits of TTRs >75% versus TTRs circa 60%. Documentation of indications for OACs needs improvement, and it is possible that OACs are underused. Further work is necessary to understand how OAC use may be optimized in these facilities.

Correction factor to improve agreement between point-of-care and laboratory International Normalized Ratio values

Results of a research project to quantify and improve the accuracy of point-of-care (POC) International Normalized Ratio (INR) values are reported. The accuracy of POC INR values relative to laboratory-measured INR values was retrospectively assessed in a cohort of patients with same-day INR determinations by both methods. Univariate linear regression was performed to derive a correction factor for POC INR values of >3; this correction factor was validated in a second cohort. In the derivation cohort (259 patients and 344 paired INR results), agreement of POC values with corresponding laboratory INR values at two specified thresholds (±15% and ±25%) was 51.2% and 66.6%, respectively; for POC INR values of >3 (n = 205), agreement was lower (24.9% and 44.9%, respectively). Univariate linear regression yielded a coefficient of 0.77 (95% confidence interval, 0.76-0.79; p < 0.001). Applying a correction factor of 0.8 to POC INR values in a validation cohort (169 patients and 209 paired INR values) significantly improved the accuracy of POC INR values of >3 relative to laboratory values (from 7% to 71.1% at the lower threshold and from 23.5% to 88.8% at the higher threshold, p < 0.0001 for both comparisons). Agreement between POC and laboratory INR results in one institution was poor, especially when POC INR values exceeded 3. Application of an institution-specific correction factor to POC INR values of >3 improved agreement with laboratory INR results but would not have significantly reduced differences in protocol-based warfarin dosage adjustments.

Quality control of oral anticoagulant therapy in Primary Care in Madrid City, Spain: CHRONOS-TAO study

ObjectivesTo determine quality control of patients with oral anticoagulant treatment recruited in Primary Care (PC) using the Rosendaal method to estimate time in therapeutic range (TTR) and comparing it with fraction of international normalized ratio (INR) in range and cross-sectional analysis (last INR registred). Material and methodA retrospective observational study based on electronic medical record in routine clinical practice. Setting: PC centers (262) in Madrid. We included all patients with acenocumarol treatment, with an INR therapeutic range established between 2 and 3. We excluded patients with valvular pathology and disrupted clinical follow up in PC (<3 INR determinations in the studied period, a period of >90 days or ≥3 periods of >60 days between 2 determinations). The final population was 49,312 patients. The variables considered were all INR values and their respective dates. TTR was calculated by the 3 methods above mentioned. We considered “therapeutic range” INR between 2 and 3 and “adjusted range” INR between 1.8 and 3.2. Optimal control for each patient was considered TTR>60%. ResultsBy using Rosendaal method, TTR was 66.8% (81.7% adjusted), with a percentage of total INR in range was 58.8% (66.5% adjusted), and, with the cross-sectional analysis, it was 70.5% (76.8% adjusted). Mean TTR was 65% (standard deviation 20.3), and the percentage of patients with TTR>60% was 63.3% (88.1% adjusted). ConclusionThe quality control of patients with oral anticoagulants in PC in Madrid is acceptable, similar or higher to other studies and pivotal trials of new anticoagulants. Compared to the Rosendaal method, total fraction of INR underestimates quality control, and cross-sectional analysis slightly overestimates it.

Analytical accuracy and precision of two novel Point-of-Care systems for INR determination

BackgroundPortable point-of-care (POC) instruments for determination of the whole blood prothrombin time (PT) have been available for the last three decades. Recently, two novel POC instruments for PT and International Normalized Ratio (INR) determination in whole blood have been manufactured. The purpose of this study was to compare INR values obtained with the novel instruments (microINR® and ProTime InRhythm™) to the INR determined with the international standard for thromboplastin rTF/09. Materials and MethodsIn 60 patients treated with vitamin K-antagonists, venous whole blood was analysed with four different types of POC instruments including the novel ones. In the same patients, citrated plasma was analysed with the international standard rTF/09 and the manual tilt tube technique for clotting time determination. We assessed the bias of the INR read from the POC instruments relative to the international standard. To study the imprecision of the two novel POC instruments, duplicate INR determinations were performed. ResultsThe results obtained with the two novel POC instruments were positively correlated with those of the international standard rTF/09. However, there was a significant bias between INR read from the novel instruments and the INR determined with rTF/09 (P<0.001). The mean bias was -13.7% (MicroINR) and -9.3% (InRhythm). The imprecision coefficient of variation in venous blood was 5.0% and 5.1%, respectively. ConclusionThe imprecision of the two novel instruments is acceptable with respect to the average within-subject variation of the INR. The accuracy of the systems is borderline and should be improved by the manufacturers.

Grado de control del tratamiento anticoagulante oral en los centros de Atención Primaria de la Comunidad de Madrid: estudio CHRONOS-TAO

ObjectivesTo determine quality control of patients with oral anticoagulant treatment recruited in Primary Care (PC) using the Rosendaal method to estimate time in therapeutic range (TTR) and comparing it with fraction of international normalized ratio (INR) in range and cross-sectional analysis (last INR registred). Material and methodA retrospective observational study based on electronic medical record in routine clinical practice. Setting: PC centers (262) in Madrid. We included all patients with acenocumarol treatment, with an INR therapeutic range established between 2 and 3. We excluded patients with valvular pathology and disrupted clinical follow up in PC (<3 INR determinations in the studied period, a period of>90 days or≥3 periods of>60 days between 2 determinations). The final population was 49,312 patients. The variables considered were all INR values and their respective dates. TTR was calculated by the 3 methods above mentioned. We considered “therapeutic range” INR between 2-3 and “adjusted range” INR between 1.8-3.2. Optimal control for each patient was considered TTR>60%. ResultsBy using Rosendaal method, TTR was 66.8% (81.7% adjusted), with a percentage of total INR in range was 58.8% (66.5% adjusted), and, with the cross-sectional analysis, it was 70.5% (76.8% adjusted). Mean TTR was 65% (standard deviation 20.3), and the percentage of patients with TTR>60% was 63.3% (88.1% adjusted). ConclusionThe quality control of patients with oral anticoagulants in PC in Madrid is acceptable, similar or higher to other studies and pivotal trials of new anticoagulants. Compared to the Rosendaal method, total fraction of INR underestimates quality control, and cross-sectional analysis slightly overestimates it.

A comparative study of conventional versus new, magnesium-poor Vacutainer® Sodium Citrate blood collection tubes for determination of prothrombin time and INR

IntroductionConventional Vacutainer® Sodium Citrate blood collection tubes contain a relatively high concentration of contaminating magnesium ions, which may result in shortening of the prothrombin time (PT) and the International Normalized Ratio (INR). Recently the manufacturer of Vacutainer® Sodium Citrate tubes introduced new tubes with a magnesium-poor stopper. The magnesium concentration in the new low-Mg tubes is significantly lower than that in the conventional plastic tubes. The purpose of the present study was to compare PT and INR determined in specimens drawn with the new tubes to those drawn with the conventional tubes. Materials and MethodsVenous blood specimens were collected from 22 healthy persons and 65 patients treated with vitamin K-antagonists using conventional Vacutainer® Sodium Citrate tubes and new, low-Mg Vacutainer® tubes. PT and INR were determined with four thromboplastin reagents, i.e., three brands of recombinant human tissue factor and one brand of combined rabbit brain reagent. Magnesium concentrations were determined in the citrate plasmas with a colorimetric method. ResultsThe differences in PT, INR and International Sensitivity Index (ISI) between the two tubes were significant when using three recombinant human thromboplastin reagents, but were not significant when using the rabbit thromboplastin. The PT and INR differences between the tubes correlated with the magnesium concentration differences (P<0.001). The INR bias between the four reagents was greater for specimens drawn with conventional tubes than the INR bias for specimens drawn with the new tubes. ConclusionAgreement of INR between reagents is improved by using magnesium-poor tubes.

Hemolysis, Pump Thrombus, and Neurologic Events in Continuous-Flow Left Ventricular Assist Device Recipients

An ongoing challenge in the management of patients with heart failure who receive left ventricular assist devices (LVADs) is achieving optimal anticoagulation. Adverse prothrombotic events include hemolysis or pump thrombus (H/T) and neurologic events (NEs), and all limit the success of LVAD therapy. Our aim was to study the incidence and clinical outcomes associated with these events in a large single-center cohort. We retrospectively reviewed our prospectively collected database of all patients receiving a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD from 2005 to 2012. Demographic, clinical, and outcome data were analyzed using standard statistical methods. All adverse events were recorded. Of 193 patients receiving LVADs, we identified 39 H/T events in 26 (13.4%) patients and 22 NEs in 19 (9.8%) patients. Seventy-four percent of events occurred in the last 3 years of the series, during which time 63% of implants were placed. Of patients with H/T, 8 (31% of those having H/T, 4.1% of total) had more than 1 event and 4 (15.4% of those having H/T, 2.1% of total) underwent pump exchanges. Five (23%) patients had NEs after H/T, and 6 (32%) died as a result of the NE. Of patients with H/T, 27% had preceding episodes of infection, 31%had an international normalized ratio (INR) of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history ofclotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. Lactate dehydrogenase (LDH), plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline values. The survival at 6months (alive or having undergone transplantation) for those with a prothrombotic event compared with those without was 70% versus 75.2% (p= 0.5). The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of these events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes.

The international normalized ratio according to Owren in liver disease: Interlaboratory assessment and determination of international sensitivity index

The international normalized ratio (INR) is used to prioritize liver disease patients for transplantation. Previous studies have shown high interlaboratory variability in Quick-based INR determinations in samples of patients with liver disease. We assessed Owren-based INR reagents for analyzing INR in patients with liver disease. Further, we determined the difference between international sensitivity index (ISI) for patients on vitamin K antagonists (ISIVKA) and ISI for patients with liver disease (ISIliver). Twenty patients with liver disease were included, 10 with INR 1.8-3.6 (group A1) and 10 with INR 1.2-1.5 (group C1). Plasma from these patients was analyzed for Owren-based INR in eight Swedish laboratories using either of following reagents: SPA+, Owrens PT or Nycotest PT. To determine ISI liver, the reference thromboplastin RBT/05 and additional 41 patients with liver disease and 20 normal controls were included. ISIVKA was determined according to the WHO procedure. The difference between the ISIVKA and ISIliver was calculated. The coefficients of variance for the Owren based INR methods were 6.2% in group A1, 3.9 % in group C1 and 5.3% for all patients. The difference between ISIVKA and ISIliver were -0.4%, -0.7% and -0.2% for SPA+, Owrens PT and Nycotest PT respectively. Interlaboratory variation in INR analyses according to Owren in patients with liver disease is low and the difference between ISIVKA and ISIliver is below 10% with this method. ISIVKA can therefore be used in the INR calibration, for the Owren reagents studied, when analyzing plasma from patients with liver disease.

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

BackgroundHemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE).Methods and designThis is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment.DiscussionTo date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety.Trial registrationEudra CT. Identifier: 2009-016643-18.

Evaluation of Thrombi‐Stat MC1 for whole blood and plasma international normalized ratio in comparison with a laboratory method

The precision and comparability of the international normalized ratio (INR) analyzed by the Thrombi-Stat MC1 coagulation testing system were evaluated before using as a point-of-care testing. Three levels of control materials were used for within-run and between-run precision study. Comparison study of INR determination from citrated whole blood (INR-WB) and citrated plasma (INR-PL) analyzed by the Thrombi-Stat MC1 with those by the validated method, Sysmex® CS-2100i (INR-CS), was performed. The within-run coefficient of variations (CVs) of INR by the Thrombi-Stat MC1 were 3.60% to 4.80%. For between-run precision, the CVs were 4.26 to 4.93%. Fifty-four plasmas from patients receiving warfarin were included for comparability testing. There were good correlation and agreement between both INR-WB and INR-PL compared with INR-CS. Eighty-seven percent of INR-WB and 100% of INR-PL were within ± 0.5 units of the INR-CS. Given that the therapeutic range was INR-CS of 2-3, 3.7% of INR-WB and 5.56% of INR-PL were discordant with the INR-CS. The precision and comparability to validated method of the Thrombi-Stat MC1 were acceptable. Either citrated whole blood or plasma may be used as samples in this system. Impact on the management of patients must be taken into consideration prior to the implementation of this system.