Mean Time In Therapeutic Range Research Articles

Applying a Computer-based Warfarin Management System at a Large Tertiary Cardiovascular Center in Iran.

Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience. To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population. By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range (TTR) and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS. Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean TTR was 57.3% before and 59% after WMS implementation (mean difference, 1.64, 95% CI: -1.12 to 4.40). In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61, 95% CI: -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range. For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits.

The quality of pharmacist-led community warfarin management across 2 provinces in Canada: A cross-sectional observational study.

Guidelines for anticoagulation management services recommend personnel be specially trained in warfarin management and suggest using tools such as decision-support software. To date, there have been no Canadian studies documenting the quality of warfarin management using a similar guideline recommended approach. A cross-sectional, retrospective observational study was conducted to measure the quality of pharmacist-led warfarin management using point-of-care international normalized ratio (INR) testing and decision-support software in various ambulatory settings in Canada. Settings included 4 family health teams in Ontario and 40 community pharmacies across Nova Scotia. Quality was measured using time in therapeutic range (TTR) and was reported in 3 manners: mean TTR, median TTR and time-weighted mean TTR. The primary outcome included 963 patients. The combined mean and median TTR for the 2019 Ontario family health teams and Nova Scotia pharmacies was 74.2% and 77.3% (interquartile range 64%-87.9%), respectively. The time-weighted mean TTR was 76.3%. To the best of our knowledge, the TTR achieved by this model of care is the highest reported in Canadian general practice. Since Thrombosis Canada defines good-quality warfarin management as a TTR of 60% or greater, and many studies have reported an association between higher TTR values and lower rates of thrombosis and hemorrhage, this model of care may have significant benefits for patients. This study demonstrates the high quality of anticoagulation management provided by specially trained pharmacists using point-of-care INR testing and decision-support software. These results support expanded access to this service for all Canadians. Can Pharm J (Ott) 2024;157:xx-xx.

Modified application of SAMe-TT2R2 scoring system in Asian patients with atrial fibrillation for the selection of oral anticoagulants.

The SAMe-TT2R2 score is used for assessing anticoagulation control (AC) quality with warfarin. However, it is hard to apply SAMe-TT2R2 score in Asian patients with atrial fibrillation (AF), because it has not been proven in those populations. This study aimed to validate the SAMe-TT2R2 score in Asian patients with AF and suggest a modified SAMe- TT2R2 score for this population. We analyzed 710 Korean patients with AF who were using warfarin. The AC quality was assessed as the mean time in therapeutic range (TTR). Each component of SAMe-TT2R2 score was evaluated for the relationship with AC. Further clinical factors that predict AC were analyzed. Identified factors were re-assorted and constructed as SA2Me-TTR scoring system. Of the components of the SAMe-TT2R2 score, female, age, and rhythm control were associated with AC. Heart failure and renal insufficiency were newly identified factors associated with AC. The modified SA2Me-TTR score was reconstructed with the relevant risk factors (S, female gender, 1 point; A, age < 60 yr, 2 points; Me, medical history of heart failure, 1 point; T, treatment for rhythm control, 1 point; T, history of stroke or transient ischemic attack, 1 point; R, renal insufficiency, 1 point). The modified SA2Me-TTR score demonstrated an excellent relationship with the grading of AC. The modified SA2Me-TTR score ≤ 1 identified patients with good AC (hazard ratio 2.46, 95% CI 1.75-3.47). The modified SA2Me-TTR score was useful for guiding oral anticoagulants selection in Asian patients with AF.

SAMe-TT2R2 Score to Predict Time in Therapeutic Range of Vitamin K Antagonists in Asian and Non-Asian patients: A Systematic Review and Meta-analysis.

Sex, age, medical history, treatment, tobacco use, and race (SAMe-TT2R2) score helps detect patients at risk of suboptimal anticoagulation control. A score above two suggests poor control; however, non-Caucasian status being assigned two points might hinder the recognition of poor control in patients of other races. To evaluate the SAMe-TT2R2 score's ability to predict poor anticoagulation control [defined as time in therapeutic range (TTR) < 60-70%] in Asian and non-Asian populations on vitamin K antagonists (VKAs). We searched PubMed, Cochrane Library, Scopus, SpringerLink, and Web of Science using the keyword "SAMe-TT2R2." Articles published before April 2022 were screened. We gathered mean TTR and diagnostic accuracy data for different SAMe-TT2R2 thresholds and conducted meta-analyses using random-effects models. A total of 30 studies were included (N = 36,690). The overall mean TTR differences were -4.88 and -6.41 for the cutoffs of ≥ 3 and ≥ 4, respectively. For non-Asian patients, the mean TTR differences were -3.86, -5.12, and -8.09 for the cutoffs ≥ 2, ≥ 3, and ≥ 4, respectively. For Asian patients, the mean TTR differences were -3.99 and -4.07 for the cut-offs ≥ 3 and ≥ 4, respectively. The highest positive likelihood ratio (LR+) for the Asian subgroup was 1.17 [95% confidence interval (CI): 1.06-1.28; I2 = 0%, p heterogeneity = 0.500] at cutoff ≥4 and for the non-Asian subgroup, at cut-off ≥ 3, the LR+ was 1.24 (95% CI 1.14-1.34; I2 = 0% p heterogeneity = 0.455). The lowest LR- was found at a lower cutoff for both races (at cutoff ≥ 3 and ≥ 2 for Asian and non-Asian subgroups, respectively). The pooled results of other accuracy parameters were modest at all cutoffs, except for the sensitivity at cutoff ≥ 3 in the Asian subgroup (83.05%). Our study results suggest that a higher SAMe-TT2R2 score resulted in a greater reduction of TTR among Asian and all races. The accuracy parameters showed the highest sensitivity for poor TTR at the SAMe-TT2R2 cutoff of ≥ 3 for Asian patients. However, the ability to identify patients likely to have poor TTR was limited. Further research is needed to enhance the risk assessment for poor anticoagulation control with VKAs. The protocol of this systematic review was registered in the International Prospective Register of Scientific Reviews: PROSPERO, registration number CRD42021291865.

Outcomes of Patients with a Mechanical Heart Valve and Poor Anticoagulation Control on Warfarin.

Patients with a mechanical heart valve (MHV) require oral anticoagulation. Poor anticoagulation control is thought to be associated with adverse outcomes, but data are limited. To assess the risks of clinical outcomes in patients with a MHV and poor anticoagulation control on warfarin. We conducted a retrospective study of consecutive patients undergoing MHV implantation at a tertiary care center (2010-2019). Primary outcome was a composite of ischemic stroke, systemic embolism, or prosthetic valve thrombosis. Major bleeding and death were key secondary outcomes. We constructed multivariable regression models to assess the association between time in therapeutic range (TTR) on warfarin beyond 90 days after surgery with outcomes. We included 671 patients with a MHV (80.6% in aortic, 14.6% in mitral position; mean age 61 years, 30.3% female). Median follow-up was 4.9 years, mean TTR was 62.5% (14.5% TTR <40%, 24.6% TTR 40-60%, and 61.0% TTR >60%). Overall rates of the primary outcome, major bleeding, and death were 0.73, 1.41, and 1.44 per 100 patient-years. Corresponding rates for patients with TTR <40% were 1.31, 2.77, and 3.22 per 100 patient-years. In adjusted analyses, every 10% decrement in TTR was associated with a 31% increase in hazard for the primary outcome (hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.13-1.52), 34% increase in major bleeding (HR: 1.34, 95% CI: 1.17-1.52), and 32% increase in death (HR: 1.32, 95% CI: 1.11-1.57). In contemporary patients with a MHV, poor anticoagulation control on warfarin was associated with increased risks of thrombotic events, bleeding, and death.

Anti-Xa Assay Monitoring Improves the Precision of Anticoagulation in Venovenous Extracorporeal Membrane Oxygenation.

Unfractionated heparin (UFH) is the most used anticoagulant in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO). Its therapeutic levels are monitored using activated partial thromboplastin time ratio (aPTTr) or antifactor Xa (anti-Xa) assay. This was a retrospective, single-center, cohort study where all adult patients with viral etiology respiratory failure requiring VV-ECMO from January 2, 2015 to January 31, 2022 were included. Anticoagulation was monitored using aPTTr (until November 1, 2019) or anti-Xa assay (after November 1, 2019). We compared the accuracy and precision of anticoagulation monitoring tests using time in therapeutic range (TTR) and variance growth rate (VGR), respectively, and their impact on bleeding and thrombotic events (BTEs). A total of 254 patients, 74 in aPTTr and 180 in anti-Xa monitoring groups, were included with a total of 4,992 ECMO-person days. Accuracy was comparable: mean TTR of 47% in aPTTr and 51% in anti-Xa groups ( p = 0.28). Antifactor Xa monitoring group demonstrated improved precision with a lower variance (median VGR 0.21 vs. 1.61 in aPTTr, p < 0.05). Secondary outcome of less heparin prescription changes (adjusted rate ratio [RR] = 1.01, p = 0.01), fewer blood transfusions (adjusted RR = 0.78, p < 0.05), and ECMO circuit changes (adjusted RR = 0.68, p < 0.05) were seen with anti-Xa monitoring.

Impact of Quality and Type of Anticoagulant Treatment, and Inflammatory Biomarkers on Quality of Life and Psychological Morbidity in Patients with Atrial Fibrillation: An Exploratory Study

Background: Owing to increasing worldwide life expectancy, the step rise in the prevalence of atrial fibrillation (AF) represents an urgent public health issue. Indeed, AF can severely affect a patient's quality of life (QoL) since it is associated with serious outcomes, such as stroke, cardiac failure, and cognitive impairment/dementia, resulting in increased morbidity and mortality and a burden for health-care systems. Anticoagulation therapy prevents stroke in individuals with AF, whether with vitamin K antagonists (VKA) or direct oral anticoagulants (DOACs). So far, effective AF management is missing since its etiology is unraveled. Within the research project [Cognitive Decline Risk Profiles and Quality of Life in Atrial Fibrillation: A Longitudinal Study- 2022.072(057-DEFI/058-CE)] a pilot study was conducted to assess a dynamic cohort of AF outpatients who attended the anticoagulation clinic at Santo António University Hospital Center, a Portuguese university public hospital. In this study, QoL, distress and cognitive impairment in patients with AF was assessed considering quality and type of anticoagulant treatment. Methods: With a cross-sectional design, quality of anticoagulation therapy was measured calculating Time in Therapeutic Range (TTR) using Rosendaal method for patients under VKA (TTR&amp;gt;70% as good control); for those patients under DOAC, the presence of plasma therapeutic levels of this drug, taking into account the time of blood sampling, meant an anticoagulant treatment of quality. QoL and distress were assessed by the Atrial Fibrillation Effect on Quality-of-life Questionnaire (AFEQT) and the Depression, Anxiety and Stress Scale (DASS-21), respectively. Cognitive impairment was assessed by the Montreal Cognitive Assessment (MoCA) scale. Data on sociodemographic, clinic [medical history including quality and type of anticoagulation therapy, stroke(CHA2DS2-VASc) and bleeding(HAS-BLED) risk scores, duration of illness) and inflammatory biomarkers were also collected. Results: A total of 62 AF patients were included (mean age 74.4±10.2 years, 59.7% women) with a mean CHA2DS2-VASc of 4.3±1.6 and HAS-BLED of 2.6±1.2. Fifty patients (80.6%) were on VKA and twelve (19.4%) on DOACs (all in apixaban). Those individuals under VKA showed a mean TTR score of 77.1 ± 14.7% (67.4% with a good control) and 11 patients in apixaban presented DOAC therapeutic plasma level. Participants had an illness duration average of 16.02 years±10.62. The mean scores of AFEQT was 2.65 ± .93 showing a good QoL and for MoCA was 21.66 ± 3.90 indicating mild cognitive impairment. Regarding anxiety, depression, and stress (DASS-21) the mean scores were 4.27 ± 4.08, 6.52 ± 4.92 and 7.37 ± 5.37, respectively showing non-clinical psychological morbidity. Patients with higher plasmatic levels of C Reactive Protein (CRP) reported more depression (r= .482; p= .005) and those with a longer illness duration presented a higher level of cognitive impairment, (r= -.398; p= .001). No other associations were found between inflammatory biomarkers and psychological variables. There were significant differences according to sex, age, and illness duration, with women reporting lower QoL (p = .002), higher depression (p = .004), higher stress (p = .005) and older patients (p = .017) as well as patients under VKA and longer disease duration reporting better TTR. (p = .007). No differences were found on patients' QoL (p = .342), anxiety (p = .370), depression (p = .167) and stress (p = .117), cognitive impairment, (p = .084) between good and non-good quality of anticoagulant treatment and between VKA versus DOAC therapy (p = .444). Conclusion: The majority of the patients showed good quality of anticoagulation and QoL, but they revealed mild cognitive impairment. Patients' QoL, distress and cognitive impairment were independent of quality and type of anticoagulation treatment. Older AF patients, particularly those with longer diagnosis, should be assessed for cognitive function on a regular basis, preventing dementia and economic burden. The association of depression with higher levels of CRP in AF patients underlines the nature of these two inflammatory conditions that coexisting associate to worse outcomes. Future studies should assess cognitive function over time to unravel the pathophysiology of cognitive decline and the effect of AF treatments on cognition to optimize and personalize AF therapy.

Quality of Oral Anticoagulation with Vitamin K Antagonists and Direct Oral Anticoagulants in ‘real-World’ Patients: Lessons from a Five Years Audit Study

Background: Even with the introduction of direct oral anticoagulants (DOACs), anticoagulation clinics (ACs) stand with a key role in monitoring. Indeed, routine evaluation by health care professionals is recommended as it is with vitamin K antagonists (VKA) with adjustments in practices of anticoagulation management services. Quality of oral anticoagulation (QOA) is associated to better clinical outcomes in those patients with indications for such therapy. It is well established that patients receiving VKA therapy, maintenance of an international normalized ratio (INR) in the therapeutic range is essential for treatment efficacy and safety. It has been reported that ACs should aim for a time in therapeutic range (TTR) between 70-80% to optimize benefit and minimize the risk of adverse events. So far, QOA for DOACs is not fully established. Aim: Since few clinical data are available considering the new era of ACs, this study aims to describe actual trends and QOA of an AC at a large academic medical hospital. Methodology: We retrospectively analyzed 23275 appointments of 5 consecutive years (May 2018 to May 2023), corresponding to 930 patients that are regularly followed up at an outpatient AC of a central hospital under anticoagulation for at least 8 weeks. TTR (≥70%) determined by Rosendaal method was used for patients under AVK and for those individuals in DOACs, QOA was considered the presence of therapeutic plasma levels of the drugs after the European Heart Rhythm Association 2021 in, at least, one determination. Patients were divided according to target INR in 3 groups: Group 1 with target INR 2-3, including 809 patients mean age 65±18 years (mean±SD), majority (36.6%) with atrial fibrillation (AF); Group 2 with target INR 2.5-3.5, including 92 patients with mean age 70±11 years, majority (85.9%) with mechanical heart valves; Group 3 with target INR 3-4, including 29 patients with mean age 63±15 years, majority (55.5%) with antiphospholipid syndrome. Seventy patients were under DOACs (apixaban in 74.3%), with mean age of 71±17 years, majority (62.9%) with non-valvular AF, were included in Group 1 and all individuals were under direct inhibitors of factor Xa. Descriptive statistics (mean, standard deviation, minimum, maximum, chi-square), inferential statistics (t-test, A-Nova and effect sizes) tests were performed. Results: The 930 patient population, 52.2% female, mean age of 65±18 years and 87% in Group 1, showed a mortality of 17%. The mean recall interval between appointments was superior to 90 days in 94% of the population. The individuals who died in comparison with the survivors showed higher frequency of AF (54.1%) [ χ 2= 47.099; p&amp;lt;.001; φ=.225], were from Group 1 (93%) [ χ 2= 6.641; p=.036; φ=.085], male (59.2%) [ χ 2= 10.103; p=.001; φ=-.104] and older [76±12 vs .63±18 years (p&amp;lt;.001), respectively]. No differences were noticed in mortality between AVK and DOACs [ χ 2= 1.828; p=.401; φ=-.044], even DOAC patients being older than AVK patients (71±17 vs 65±17; p=.005), respectively. QOA associated with mortality being the individuals who died with higher frequency of no QOA (21.9% vs 13.9%) [ χ 2= 8.126; p=.004; φ=-.101] respectively. The individuals on AVK from Group 1 corresponding to 86% of total population showed a mean TTR of 76%, patients from Group 2 had a TTR of 72% and patients in Group 3 had TTR of 55%. From the individuals under DOACs, only 30% had at least one determination of plasma levels of the drug and all but one showed therapeutic levels. Comparatively with our previous studies related to the periods of 2006-2012 and 2012-2018, we noticed a significant decrease in patient population / appointments size (2087/ 61988) (1587/ 37931),(p &amp;lt;.001) with an increase of TTR in Group 1 (1927/1430 patients) (83% /72%) and Group 2 (120/125 patients) (74% / 69%) but a TTR decrease in Group 3 (40 / 32 patients) (54% / 60%) (p &amp;lt;.001). respectively. Mortality in the 2012- 2018 period was 18%. Conclusions and Discussion: The trends of decreasing the number of anticoagulated patients at our AC with an overall good quality of monitoring but with a low percentage of individuals under DOACs suggests that the majority of anticoagulated population is on these drugs without routine follow up in opposition to the recent recommendations. Our study underlines the importance of the quality of anticoagulation monitoring on mortality that was no different from the previous years before SARS-CoV- 2 pandemic nor between AVK and DOACs.

Antiphospholipid Antibody Syndrome (APS) Pediatric Patient Outcomes on Warfarin

Background: Antiphospholipid antibody syndrome (APS) is an acquired thromboembolism (TE) risk factor and places patients at very high risk of recurrent TE. APS diagnosis requires venous (deep vein thrombosis (DVT) or pulmonary embolism (PE)) or arterial thromboembolism and laboratory diagnosis including persistently positive lupus anticoagulant (LA) or elevated anticardiolipin (aCL) and/or beta 2 glycoprotein I (B2GPI) antibodies tested 12 weeks apart. Vitamin K antagonist (warfarin) is the standard of care anticoagulant to reduce risk of TE recurrence in APS patients. Warfarin is dosed based on the International Normalized Ratio (INR) with established therapeutic ranges for optimal efficacy and safety. The reported time in therapeutic range (TTR) varies greatly across specialties with an average TTR of 50-55%. However, it is often difficult to maintain target INR in APS. Furthermore, there is limited data evaluating pediatric patients with APS and their TTR on warfarin and outcomes. Aim: To evaluate the relationship of APS status to TTR and outcomes of patients &amp;lt; 21 years of age with APS who are on warfarin anticoagulation. Methods: This was a single center analysis of APS patients between July 2019 and May 2022 who were enrolled in a multi-center prospective study of pediatric patients on warfarin therapy, eKITE (electronic KidClot Thrombophilia Education). The study included an online learning series regarding warfarin management. Home INR meters and test strips were provided to all patients to perform INR testing. INR values were reported by patients and recorded. Demographic and clinical data was extracted from the electronic medical record, target INR was set by the treating provider, and TTR was calculated as a surrogate for safe, effective warfarin management. Results: Nine patients (n=9) with APS were identified for this analysis, mean age 16.7 years (range 12-19 years). Demographic and laboratory findings are summarized in Table 1. Most patients had secondary APS due to systemic lupus erythematous (SLE) 78% (n=7) and 22% (n=2) had other primary diagnoses. APS antibody status included single positive in 67% (n=6), double positive in 22% (n=2), and triple positive in 11% (n=1). More specifically, APS criteria were met by persistently elevated LA in 78% (n=7), aCL IgM in 22% (n=2) with overall mean aCL IgM of 34.4 MPL^ (range 9.9-127.9), B2GPI IgG in 11% (n=1) with overall mean B2GPI IgG SGU* of 13.1 (range 0.9-63.3), and B2GPI IgM in 22% (n=2) with overall B2GPI IgM mean of 32.5 SGU (range 3.3-190.9). At time of presentation 67% (n=6) of patients had DVT, 44% (n=4) had PE, 11% (n=1) had arterial TE, and 22% (n=2) presented with DVT &amp; PE. Mean TTR for all patients was 56%. TTR for single positive APS was 66%, double positive APS 39%, and triple positive APS 33%. TTR for secondary APS (SLE) and non-SLE diagnoses was 53% and 68% respectively. Mean dose changes were 11 (range 0-48) with one single positive LA patient requiring 48 dose changes, and two patients with single positive LA not requiring any dose changes. Two patients (22%) developed recurrent clot. One triple positive APS patient developed two DVTs and one non-SLE patient developed recurrent arterial TE. Three patients (33%) had minor bleeding events including mild epistaxis and hematemesis not requiring intervention. One patient (11%) had a major bleeding event, hemoperitoneum from pseudoaneurysm extravasation, while resuming warfarin during post-operative period, and required takeback surgery with sub-therapeutic INR 1.5 at the time of event. Conclusion: The mean TTR for pediatric patients with APS is similar to what is reported in other populations despite the challenge of managing warfarin in this group where the INR may be affected by primary disease modifying medications or disease flares. The risk of recurrent TE remains high in APS patients. Home INR monitors are a safe and effective strategy in managing warfarin anticoagulation in APS patients, reducing time and laboratory monitoring burden for frequent dose changes, which ultimately improves quality of life.Optimizing TTR is important to decrease risk of recurrent TE or bleeding in these high risk APS patients.

Comparing follow-up of patients with vitamin K antagonists in a health center: pre- and post- COVID-19 pandemic

Introduction and objectives: During the COVID-19 pandemic, the follow-up of patients treated with vitamin K antagonists (VKAs) may have been affected. This study aims to compare how these patients were monitored preand post-COVID-19 pandemic and understand the impact of non-face-to-face appointments on their follow-up. Methods: We conducted a retrospective cohort study in a Portuguese Health Center. The study included patients treated with VKAs and followed at the Health Center for international normalized ratio (INR) monitoring between March 2019 and March 2021. Data collected: sex, age, type of VKA; INR; date of INR assessment, type of appointment (face-to-face or phone/e-mail). Rosendaal’s method was used to calculate pre-COVID-19 and post-COVID-19 time in therapeutic range (TTR). Good TTR control was defined if values ≥ 70%. Results: 44 patients were included. The mean TTR in the pre-COVID-19 period was 64.55% (95% CI: 58.10 - 71.00%). The post-COVID-19 mean was slightly higher (+ 2.26%), 66.81% (95% CI: 59.66 - 73.97%), but the difference was not statistically significant (p = 0.576). The use of non-face-to-face appointments did not contribute to worsening post-pandemic TTR, showing no lower follow-up than during pre-pandemic period in which all contacts were face-to-face [CI (95%) -0.397 - 0.196 for a reference range -0.489 - 0.693]. Conclusions: The TTR value in both periods was similar and lower than the value defined for effective hypocoagulation. The use of non-face-to-face consultation in the post-COVID-19 period does not seem to have influenced the quality of hypocoagulation.

Quality of anticoagulation and outcomes after mechanical aortic valve replacement in patients with atrial fibrillation: a nationwide cohort study

Abstract Background Mechanical aortic valve replacement (AVR) remains predominant treatment approach for younger patients in need of aortic valve operation. However, little is known about the success of the required Vitamin K Antagonist (VKA) treatment and its relation to adverse events. Purpose We assessed the quality of VKA treatment prior to ischemic events and major bleeding episodes after mechanical AVR in AF patients. Methods The registry-based FinACAF study combining data from several Finnish health care registers covers all patients diagnosed with atrial fibrillation (AF) during 2007–2018 in Finland. In the present study, we included patients undergoing mechanical AVR before or after the AF diagnosis. Hazard ratios (HR) of first-ever ischemic stroke, any bleeding, intracranial bleeding, and myocardial infarction (MI) after AVR were estimated with Fine-Gray model adjusted for known bleeding and stroke risk factors. Results We identified 1086 patients (27.1% female, median age 62.8 (IQR 56.2–68.3) years) with mechanical AVR and AF diagnosis, either before (58.8%) or after (41.2%) the operation, and without prior bleeding episode, ischemic stroke, or MI. Cumulative incidence estimates at 10 years after AVR were 12.8% for ischemic stroke, 27.9% for significant bleeding, 5.8% for intracranial hemorrhage (ICH), and 7.2% for MI. International Normalized Ratio (INR) was &amp;lt;2.0 during 27.9–33.9% of ischemic events and lower mean Time in Therapeutic Range (TTR) with INR target ≥2.0 was associated with subsequent higher stroke occurrence (standardized adjusted HR 1.23 (1.03–1.49) for lower TTR, p=0.030, Figure 1). INR was &amp;gt;3.5 during 23.4–24.3% of major bleeding events and lower mean TTR (INR target 2.0–3.5) was associated with subsequent bleeding episode (adjusted HR 1.20 (1.03–1.41), p=0.021, Figure 2). Mortality was high (10-year estimated survival 71.1%), and lower mean TTR (INR target 2.0–3.5) was associated with higher mortality (adjusted HR 1.56 (1.39–1.72), p&amp;lt;0.001). Conclusions Adverse events after mechanical AVR are frequent in AF patients and mortality is high. Suboptimal mean TTR appears to identify the patients at high risk for both bleeding episodes and ischemic stroke.Figure 1.Figure 2.

Evaluation of antithrombotic treatment in institutionalized geriatric patients with nonvalvular atrial fibrillation

ObjectiveThe goals of this study were to analyze the type of antithrombotic treatment administered to institutionalized patients with nonvalvular atrial fibrillation (and any ensuing complications) and to evaluate the degree of anticoagulation control achieved with vitamin K antagonists. MethodThis was a prospective observational follow-up study carried out in seven elderly care facilities during 2016. Patients with nonvalvular atrial fibrillation were evaluated for their antithrombotic therapy and any embolic or hemorrhagic events, as well as for mortality. Subjects on anticoagulation treatment with VKAs were evaluated for anticoagulation control, with control considered poor if the mean time in therapeutic range was < 65% when measured with Rosendaal's method or < 60% when determined by the direct method. ResultsOf the 699 residents evaluated, 20.6% had a diagnosis of NVAF. Average age was 85.83 years. Both the cardioembolic (mean CHA2DS2-VASc score: 4.79), and the hemorrhagic (mean HAS-BLED score: 3.04) risk were high. Fifty percent received anticoagulation treatment, mainly with vitamin K antagonists, of whom at least 56% were not within the therapeutic range. Sixteen percent of the residents, the oldest and most functionally and cognitively dependent ones, had not been prescribed any antithrombotic therapy. A higher frequency of hospital admissions induced by cardiovascular and bleeding events was found in these residents, although differences were not statistically significant. ConclusionsHalf of institutionalized geriatric patients with nonvalvular atrial fibrillation are anticoagulated, a third on antiplatelet therapy, and some without any antithrombotic treatment. This study showed that as functionality decreases, treatment strategies are increasingly aimed at therapeutic deintensification. Given that the degree of anticoagulation control with vitamin K antagonists is inadequate in 56% of cases, it is essential to monitor the time in therapeutic range to optimize treatment as needed.

Assessment of the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation: A systematic review and meta-analysis.

The present study aimed to investigate the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation. This is a systematic review and meta-analysis written on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches at MEDLINE, EMBASE, Scopus and LILACS electronic databases were carried out on February 13, 2023, using the descriptors "Patient Medication Knowledge", "Patient Education as Topic", "Health Education", "Patient Education" and Warfarin. The steps of selection, data extraction and quality analysis of articles were performed independently by two reviewers. The analysis was performed considering patient knowledge as a possible modifier of time in therapeutic range (TTR). The meta-analysis included studies that reported the correlation coefficient (Pearson or Spearman) between patient knowledge and TTR. A subgroup analysis was performed according to questionnaires employed to measure patient knowledge. Twelve studies were selected with an overall sample size of 7634 participants and mean age 58.2 (standard deviation (SD)±12,8) years. Eleven (92.0%) cross-sectional studies. The mean TTR was 57.8% (SD±11,3%) and the average level of knowledge was 60.4%. The meta-analysis indicated that patient level of knowledge on warfarin therapy was moderately associated with TTR (rs = 0.435; 95% confidence interval (CI) = 0.163-0.645; I2 = 96%). Subgroup analysis indicated association between knowledge level and TTR in studies employing the OAK test (rs = 0.617; 95% CI = 0.192-0.847; I2 = 97%) and the AKA (rs = 0.269; 95% CI = 0.002 to 0.501; I2 = 94%). However, the subgroup analysis presented no significant difference between them (p = 0.14). The meta-regression showed a non-significant negative effect of age on the correlation (estimate = -0.028, 95% CI = -0.073 to 0.016, p = 0.207). No publication bias was noted (p = 0.881). To our knowledge, this is the first systematic review and meta-analysis gathering evidence about the relationship between the level of patient knowledge on oral anticoagulation with warfarin and TTR. The implementation of structured and patient-centered educational interventions is essential to effectively increase the level of patient knowledge and, thus, to improve the quality and safety of warfarin therapy. Systematic review registration number: PROSPERO CRD42023398030.

Lower dose direct oral anticoagulation or warfarin in atrial fibrillation. Which one is the best when time on therapeutic range information is available?

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Helsinki and Uusimaa Hospital District (TYH2019309) and The Finnish Foundation for Cardiovascular Research Background and aims Elderly patients with atrial fibrillation (AF) and patients with renal failure – for example – are recommended to use reduced doses of direct oral anticoagulants (DOACs) to minimize risk of ischemic stroke and hemorrhagic complications. However, it is not known whether DOACs used with reduced doses are better than warfarin when the quality of warfarin treatment is available by means of time in therapeutic range (TTR). Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients that combines data from several Finnish health care registers. Here all new-onset AF patients from 2011 to 2018 on reduced dose DOAC in Finland and patients on warfarin with TTR data were analyzed. Comorbidities, concomitant medications and CHA2DS2-VASc -scores were recorded until date of AF diagnosis. OAC purchases from diagnosis of AF to the end of study were analyzed. ICD-10 diagnoses for stroke (ischemic or hemorrhagic) or transient ischemic attack during OAC-use were analyzed until maximum follow-up of 730 days. Crude rates of stroke as well as weighted rates are provided. To avoid confounding by baseline characteristics as well as medications, an inverse probability of treatment weighted analysis was made. For warfarin users with sufficient laboratory data, time in therapeutic range (TTR) was calculated and patient quartiles by TTR were assigned. Results Altogether, 52 204 new-onset AF patients with OAC therapy (46.1 % male, mean age 75.7 years, 43 549 on warfarin - with mean TTR 66%, median TTR 72%) were followed for 91 549 patient-years (py). Rate of stroke among patients on lower dose DOACs was 5.2/100 patient years (py) for dabigatran (n=2 672), 4.3/100 py for apixaban (n=3 936), 3.9 /100 py for rivaroxaban (n=1 866). In the TTR-quartiles of patients on warfarin, the rates of stroke were 9.3, 7.2, 5.5 and 4.3 /100 py from the lowest (mean TTR 32%) to the highest quartile (mean TTR 90%), respectively. The weighted rates of stroke were 5.1, 3.5 and 3.1/100 py for dabigatran, apixaban and rivaroxaban, respectively and for warfarin from the lowest to the highest quartile: 8.7, 7.0, 5.4 and 4.1/100 py. Figure provides survival probabilities of the OAC groups with confidence limits. Conclusion In AF patients treated with OAC, the rates of stroke were highest among patients on warfarin at the lowest TTR quartiles, while the differences between high TTR groups and lower dose DOACs were only modest.

How good is time-in-therapeutic-range defined warfarin treatment compared to standard dose direct oral anticoagulants? Incidence of stroke in atrial fibrillation in a nationwide registry study

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): The Finnish Foundation for Cardiovascular Research, and Helsinki and Uusimaa Hospital District research fund. Background and aims Direct oral anticoagulants (DOACs) have largely replaced warfarin in patients with atrial fibrillation (AF) to reduce risk of stroke. However, it is not known whether DOACs are more efficacious in preventing stroke or safer than good-quality warfarin treatment with high time in therapeutic range (TTR). Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients that combines data from several Finnish health care registers. We analyzed all new-onset AF patients in Finland from January 2011 to December 2018 with laboratory data available. Comorbidities, concomitant medications and CHA2DS2-VASc -scores were recorded until date of AF diagnosis. OAC purchases from diagnosis of AF to the end of study were analyzed. ICD-10 diagnoses for stroke (ischemic or hemorrhagic) or transient ischemic attack during OAC use were analyzed until maximum follow-up of 730 days. Confounding factors by baseline characteristics as well as medications were taken in account by use of an inverse probability of treatment weighted analysis. For warfarin users, time in therapeutic range (TTR) was calculated and patient quartiles by TTR were assigned. Rate of stroke in different TTR quartiles for warfarin users were compared to standard dose dabigatran (150 mg bd.), apixaban (5mg bd.) and rivaroxaban (20mg od.). Results Altogether, 74 008 new-onset AF patients with OAC therapy (50.4 % male, mean age 73.0 years, 43 549 on warfarin, with mean TTR 66% and median TTR 72%) were followed for 109 143 patient years (py). Rate of stroke among patients with standard dose direct oral anticoagulants was 6.0/100 py for dabigatran (n=4545), 6.2/100 py for apixaban (n=12 426) and 4.0/100 py for rivaroxaban (n=12 950). In the TTR quartiles of patients on warfarin, rates of stroke were 9.3, 7.2, 5.5 and 4.3/100 py from the lowest (mean TTR 32%) to the highest quartile (mean TTR 90%), respectively. The weighted rates of stroke were 6.3, 6.1 and 4.5/100 py for dabigatran, apixaban and rivaroxaban, respectively, and for warfarin from the lowest to the highest quartile: 8.8, 7.0, 5.5 and 4.2/100 py, respectively. The Figure provides survival probabilities (crude rates) of stroke with confidence intervals of the analysed OAC groups. Conclusion Rates of stroke were evidently the highest among patients on warfarin in the two lowest TTR quartiles, while the differences between high TTR groups and standard dose DOACs were only modest.

Torque Teno Virus Load Predicts Opportunistic Infections after Kidney Transplantation but Is Not Associated with Maintenance Immunosuppression Exposure.

Measuring the non-pathogenic Torque Teno Virus (TTV) load allows assessing the net immunosuppressive state after kidney transplantation (KTx). Currently, it is not known how exposure to maintenance immunosuppression affects TTV load. We hypothesized that TTV load is associated with the exposure to mycophenolic acid (MPA) and tacrolimus. We performed a prospective study including 54 consecutive KTx. Blood TTV load was measured by an in-house PCR at months 1 and 3. Together with doses and trough blood levels of tacrolimus and MPA, we calculated the coefficient of variability (CV), time in therapeutic range (TTR) and concentration/dose ratio (C/D) of tacrolimus, and the MPA-area under the curve (AUC-MPA) at the third month. TTV load at the first and third month discriminated those patients at risk of developing opportunistic infections between months 1 and 3 (AUC-ROC 0.723, 95%CI 0.559-0.905, p = 0.023) and between months 3 and 6 (AUC-ROC 0.778, 95%CI 0.599-0.957, p = 0.028), respectively, but not those at risk of acute rejection. TTV load did not relate to mean tacrolimus blood level, CV, TTR, C/D and AUC-MPA. To conclude, although TTV is a useful marker of net immunosuppressive status after KTx, it is not related to exposure to maintenance immunosuppression.

SAMe-TT2R2 to Predict Clinical Outcomes and Time in Therapeutic Range in Patients on Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

The SAMe-TT2R2 score identifies patients on vitamin K antagonists (VKAs) who are more likely to have poor time in therapeutic range (TTR); however, the association between SAMe-TT2R2 and clinical outcomes remains controversial. The objective is to assess the association of SAMe-TT2R2 score with clinical outcomes and poor TTR in patients on VKAs. We searched using the term "SAMe-TT2R2." Original articles reporting clinical outcomes and SAMe-TT2R2 scores before October 2021 were included. Odds ratios (ORs) of clinical outcomes, diagnostic accuracy parameters of poor TTR (<60%-70%), and mean TTR were extracted. Meta-analysis was performed using random-effects models. Ten studies were included (N = 22 894); 4 showed pooled changes in TTR of -3.61% (95% CI:-4.88% to -2.35%) and -3.98% (95% CI: -6.08% to -1.87%) at SAMe-TT2R2 scores ≥2 and ≥3, respectively, compared with lower scores. The diagnostic accuracy parameters for poor TTR were too heterogeneous to conclude. SAMe-TT2R2 ≥3 significantly correlated with all adverse events (OR = 1.43 [95% CI: 1.29-1.54; P < 0.001]), composite thromboembolism (OR = 1.53 [95% CI: 1.19-1.97; P = 0.001]), and composite bleeding (OR = 1.33 [95% CI: 1.12-1.59; P = 0.001] regardless of the indication, while an SAMe-TT2R2 ≥2 significantly correlated with mortality (OR = 1.32 [95% CI: 1.02-1.70; P = 0.033]). We found no relationship between an SAMe-TT2R2 ≥3 and mortality or between a score ≥2 and clinical outcomes. Patients on VKAs with SAMe-TT2R2 ≥3 experienced more adverse events, bleeding, and thromboembolism compared with patients who had an SAMe-TT2R2 <3. However, the score had limited and inconclusive predictability for poor TTR in the study.

SAIL study of stroke, systemic embolism and bleeding outcomes with warfarin anticoagulation in non-valvular atrial fibrillation (S4-BOW-AF).

In patients with non-valvular atrial fibrillation (NVAF) prescribed warfarin, the association between guideline defined international normalised ratio (INR) control and adverse outcomes in unknown. We aimed to (i) determine stroke and systemic embolism (SSE) and bleeding events in NVAF patients prescribed warfarin; and (ii) estimate the increased risk of these adverse events associated with poor INR control in this population. Individual-level population-scale linked patient data were used to investigate the association between INR control and both SSE and bleeding events using (i) the National Institute for Health and Care Excellence (NICE) criteria of poor INR control [time in therapeutic range (TTR) <65%, two INRs <1.5 or two INRs >5 in a 6-month period or any INR >8]. A total of 35 891 patients were included for SSE and 35 035 for bleeding outcome analyses. Mean CHA2DS2-VASc score was 3.5 (SD = 1.7), and the mean follow up was 4.3 years for both analyses. Mean TTR was 71.9%, with 34% of time spent in poor INR control according to NICE criteria.SSE and bleeding event rates (per 100 patient years) were 1.01 (95%CI 0.95-1.08) and 3.4 (95%CI 3.3-3.5), respectively, during adequate INR control, rising to 1.82 (95%CI 1.70-1.94) and 4.8 (95% CI 4.6-5.0) during poor INR control.Poor INR control was independently associated with increased risk of both SSE [HR = 1.69 (95%CI = 1.54-1.86), P < 0.001] and bleeding [HR = 1.40 (95%CI 1.33-1.48), P < 0.001] in Cox-multivariable models. Guideline-defined poor INR control is associated with significantly higher SSE and bleeding event rates, independent of recognised risk factors for stroke or bleeding.

Anticoagulation Control and Major Adverse Clinical Events in Patients with Operated Valvular Heart Disease with and without Atrial Fibrillation Receiving Vitamin K Antagonists.

Good quality anticoagulation among patients with operated valvular heart disease is needed to reduce ischaemic and thromboembolic complications. There is limited evidence regarding factors that affect anticoagulation control in patients implanted with mechanical or tissue prosthetic valve(s). To examine the quality of and factors that affect anticoagulation control, major adverse clinical events and all-cause death in operated valvular heart disease patients with and without atrial fibrillation who are receiving a vitamin K antagonist. Quality of anticoagulation were retrospectively assessed among 456 operated valvular heart disease patients [164 (36%) with AF and 290 (64%) without AF] via time in therapeutic range (TTR) (Rosendaal method) and percentage of INRs in range (PINRR) over a median of 6.2 (3.3-8.5) years. VHD was defined by the presence of a mechanical or tissue prosthetic valve at the mitral, aortic, or both sites. Mean age 51 (14.7), 64.5% men. Most (96.1%) had a mechanical prosthesis and 64% had aortic valve replacement. Overall, mean TTR was 58.5% (14.6) and PINRR was 50.1% (13.8). Operated valvular heart disease patients with AF had significantly lower mean TTR and PINRR (TTR: 55.7% (14.2) vs. 60.1% (14.6); p = 0.002, respectively, PINRR: 47.4% (13.5) vs. 51.6% (13.7); p = 0.002, respectively), and a lower proportion of TTR ≥ 70%, despite a similar number of INR tests compared to those without AF. Predictors of TTR < 70% were female sex, AF and anaemia/bleeding history. Significantly higher proportions of operated valvular heart disease patients with AF died (20.7% vs. 5.8%; p < 0.001), but ≥1 MACE rates were similar between the two groups. Operated valvular heart disease patients with AF at baseline have poorer anticoagulation control compared to those without AF. The presence of concomitant AF, anaemia/bleeding history and female sex independently predicted poor TTR. Stringent INR monitoring is needed to improve anticoagulation control and prevent major adverse clinical events in patients with operated valvular heart disease.

Direct oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation and CKD G3-G5D.

The use of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation (NVAF) and advanced chronic kidney disease (CKD) including dialysis is growing. Several studies have shown favorable results of DOAC compared with warfarin regarding bleeding risk but no difference in stroke protection. However, these studies had poor time in therapeutic range (TTR), in the warfarin comparison group. This was a Swedish national cohort study investigating the risk of ischemic stroke and major bleeding on DOAC compared with warfarin in patients with NVAF, glomerular filtration rate category 3-5D (G3-G5D), kidney transplant recipients excluded, between 2009 and 2018. Data extracted from high-quality national healthcare registries including the Swedish Renal Registry, AuriculA (the Swedish national quality register for AF and anticoagulation) and The Stroke Register. At enrolment, of 2453 patients 59% were treated with warfarin (mean TTR 67%) and 41% with DOAC. Overall, 693 (28.3%) had G3, 1113 (45.4%) G4, 222 (9.1%) G5 and 425 (17.3%) G5D. DOAC compared with warfarin showed lower hazard of major bleeding [hazard ratio 0.71 (95% confidence interval 0.53-0.96)] but no difference in ischemic stroke risk. Mortality was increased during DOAC treatment [1.24 (1.01-1.53)], presumably not a causal association since fewer fatal bleedings occurred on DOAC. DOAC treatment, compared with warfarin, is associated with almost 30% lower risk of bleeding in patients with NVAF and CKD G3-G5D. The stroke risk is comparable between the treatments. This is the first study comparing DOAC and well-managed warfarin (TTR 67%) in advanced CKD. Ongoing and planned randomized controlled trials need to confirm the possible benefit of DOAC.