Lower Time In Therapeutic Range Research Articles

Time in therapeutic range and risk of preeclampsia in chronic hypertensive pregnant women.

Pregnancy Hypertensive Disorders (PHD), particularly Preeclampsia (PE), are significant contributors to maternal-fetal morbidity and mortality, with chronic arterial hypertension (CH) being a major risk factor. The prevalence of CH has risen alongside obesity and advanced maternal age. While antihypertensive treatment mitigates adverse pregnancy outcomes, the duration of effective blood pressure (BP) control, termed Time in Therapeutic Range (TTR), has not been extensively studied in pregnant women. TTR, reflecting the proportion of time BP remains within target ranges, predicts long-term cardiovascular and renal events in the general population but remains unexplored in pregnancy. This study investigates the association between TTR, assessed through office BP (OBP) and ambulatory BP monitoring (ABPM), and PE development in pregnant women with CH. In a retrospective longitudinal study, data from 166 pregnant women with HA referred to our hospital analyzed. BP was measured using OBP and ABPM from 10 weeks of gestation, with TTR calculated as the percentage of visits where BP remained within target ranges. The study defined four TTR control groups: 0%, 33%, 50-66%, and 100%. Results showed that 28% of the participants developed PE, with a higher incidence correlating with lower TTR in ABPM. TTR in ABPM was a significant predictor of PE risk, with the best-controlled group (100% TTR) demonstrating a 92% reduced risk compared to those with 0% TTR. The agreement between OBP and ABPM TTR was low, emphasizing the importance of ABPM for accurate BP monitoring in pregnancy. This study indicates that integrating ABPM for TTR assessment in high-risk pregnancies has the potential to reduce maternal and fetal complications.

Effect of Previous INR Control during VKA Therapy on Subsequent DOAC Adherence and Persistence, in Patients Switched from VKA to DOAC.

Current guideline suggests a switch from vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) in patients with low time in therapeutic range (TTR < 70%). Poor international normalized ratio (INR) control may be the result of poor compliance, and might therefore be associated with subsequent DOAC intake. Therefore, this study evaluates the effect of previous TTR and other measures of INR control on DOAC nonadherence and nonpersistence, in patients who switched from VKA to DOAC. A total of 437 patients who switched from VKA to DOAC between 2012 and 2019 were included using data from Certe Thrombosis Service, IADB.nl pharmacy community database University Groningen, and Statistics Netherlands. DOAC prescriptions were used to determine nonadherence and nonpersistence. INR control (i.e., TTR, time under therapeutic range [TUR], and INR variability) was assessed during the last 180 days of VKA use. Multivariable regression models were applied to determine the association between INR control and DOAC nonpersistence/nonadherence. On VKA, 67.7% of the patients had a TTR below 70%. DOAC nonpersistence was 39.8% (95% confidence interval [CI]: 33.4-45.5%) during a median follow-up of 34.4 months (interquartile range: 19.1-49.2). Approximately 80% of persistent patients were DOAC-adherent. Low TTR was not associated with DOAC nonpersistence (hazard ratio: 1.14, 95% CI: 0.69-1.87) and DOAC nonadherence (odds ratio: 1.38, 95% CI: 0.67-2.84), nor were TUR and INR variability. Previous INR control during VKA therapy is not associated with subsequent DOAC nonadherence and nonpersistence. This study suggests that INR control on VKA cannot, and therefore should not, be used for predicting DOAC adherence or persistence.

Real-world evidence that among atrial fibrillation patients warfarin is associated with reduced nonelective admissions compared with those on DOACs.

Randomized trials show inconsistent estimates on risks of direct-acting oral anticoagulants (DOACs) versus warfarin in bleeding and mortality for atrial fibrillation (AF) patients. Trials are confounded by additional DOAC adherence support, while warfarin has a low time in therapeutic range. Few real-world studies compared emergency hospitalization risk between DOAC and warfarin users in AF. This study aimed to determine emergency hospitalization risk for AF patients on DOACs or warfarin in real-world settings. A tapered-matched real-world cohort extracted data from 412 English general practices' primary care records linked with emergency department (ED) and hospitalization data from the ECLIPSE database. AF patients with new DOAC or warfarin prescriptions were included. The primary outcome was all-cause ED attendance; the secondary outcomes were ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months. Weighted Cox regression estimated relative risk difference. 39 201 DOAC patients were matched with 13 145 warfarin patients. DOAC patients had a 25% higher likelihood of attending ED (odds ratio 1.25; 95% confidence interval [CI] 1.01-1.55). DOAC use also associated with higher ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months: 1.41 (95% CI 1.00-1.98), 1.26 (1.00-1.57), and 1.54 (1.01-2.34), respectively, with p-values < .05. DOACs for AF thromboprophylaxis are associated with the increased risk of ED attendance, recurrent hospitalization, and numerical rise in ED re-attendance and first nonelective hospitalization compared to warfarin. However, these real-world data cannot establish if this difference results from medication adherence, lack of regular warfarin clinic monitoring, unmeasured confounders, or fundamental agent efficacy disparities.

Supra-therapeutic Anticoagulation with Warfarin: A Cross-sectional Study.

To identify the extent and associated factors for patients with prolonged prothrombin time, international normalized ratio (PT-INR), and the dosage modifications were carried out with warfarin. Studies evaluating patients on warfarin with supratherapeutic anticoagulation are limited. It is vital to understand the management strategies for patients receiving warfarin who are bleeding and those with only supratherapeutic PT-INR. To evaluate the factors associated with supratherapeutic anticoagulation without bleeding with warfarin. A cross-sectional study was carried out on patients receiving long-term warfarin with at least one PT-INR value > 3.2. Percent time in therapeutic range (TTR) was calculated and National Institute for Health and Care Excellence (NICE) guidelines were adhered to defining anticoagulation control into good (> 65%) and poor (< 65%). One hundred and forty-four patients were recruited. Nearly half of the study population had PT-INR values between 3.2 and 3.9. On average, individuals had at least 4 times PT-INR values in the supratherapeutic range. Elderly patients were observed with a significant trend of supratherapeutic INR. Duration of therapy was significantly correlated with the risk of PT-INR > 4. Lower TTR was observed in patients with frequent PT-INR > 4 and those patients had significantly poor anticoagulation control. Duration of warfarin therapy and HAS-BLED scores were observed to be significant predictors of supratherapeutic INR. Large variations were observed in the modifications of warfarin dose carried out at various supratherapeutic INR values and consequently PTINR values. We observed that the majority of patients with supratherapeutic INR had their INR values between 3.2 and 3.9. Elderly patients, with higher HAS-BLED scores and prolonged duration of warfarin therapy, were observed with an increased risk of supratherapeutic anticoagulation. Careful dosage modifications are needed particularly in high-risk categories as mentioned above.

Lower Time in Therapeutic Range Relates to a Worse Kidney Graft Outcome

Tacrolimus has a narrow therapeutic margin. Maintaining tacrolimus blood levels in the appropriate range is difficult because of its intrapatient variability. In fact, greater blood level variability has been related to worse kidney graft outcome, but only measuring variability does not consider the therapeutic range goal. Determining the time in therapeutic range (TTR) using the Rosendaal method allows dose optimization by considering the adverse events associated with both supratherapeutic and subtherapeutic doses. Some previous studies in kidney and lung transplantation have shown that the measurement of TTR has been related to the subsequent graft outcome. We performed a single-center, observational study including 215 consecutive kidney transplants performed in our center. The percentage of time that the patient remained with levels above 6 ng/mL between months 3 and 12 (%TTR3-12) was calculated using the Rosendaal method. A lower %TTR3-12 was associated with a higher risk of acute rejection (area under the receiver operating characteristic curve, 0.614; 95% confidence interval [CI], 0.513-0.714; P=.018) and with a higher risk of having a 1-year glomerular filtration rate < 30 mL/min/1.73 m2 (area under the receiver operating characteristic curve, 0.676; 95% CI, 0.542-0.811; P=.014). The lowest tertile of %TTR3-12 was independently associated with a higher risk of death-censored graft loss (hazard ratio, 10.773; 95% CI, 1.315-88.264; P=.027) after adjusting by 1-year glomerular filtration rate, expanded criteria donation, and acute rejection throughout the first year. To conclude, measuring TTR after kidney transplant is an easy way to estimate the time of exposure to adequate levels of tacrolimus and relates to kidney graft outcome.

Lower tacrolimus time in therapeutic range is associated with inferior outcomes in adult liver transplant recipients.

Previous studies on solid organ transplantation have reported that a low time in therapeutic range (TTR) of tacrolimus increases the risk of poor outcomes. However, the reproducibility of the findings in liver transplantation has not yet been confirmed. The TTR, coefficient of variation (CV) and standard deviation (SD) were calculated for 207 adult liver transplant patients from the date of transplantation until the first episode of acute rejection (AR), graft loss, acute kidney injury (AKI), biliary complications, infection or the last follow-up. Kaplan-Meier curves, log-rank tests and Cox regression analyses were performed. Sixty-one (29.5%) patients reached the composite endpoint of AR, biliary complications and graft loss. The log-rank test indicated that the low TTR group had an increased risk of the composite endpoint (P < 0.001), AKI (P < 0.001) and infection (P < 0.001). Multivariate Cox regression analyses revealed that a 10% decrease in TTR was associated with an increased hazard for composite endpoint (hazard ratio [HR]: 1.185, P = 0.010), AKI (HR: 1.355, P < 0.001) and infection (HR: 1.357, P < 0.001). Unexpectedly, SD and CV demonstrated no association with the above-mentioned inferior outcomes. Compared with SD and CV, the TTR of tacrolimus was more correlated with inferior outcomes and may be a novel indicator for predicting the prognosis of liver transplantation.

Blood pressure control measures and cardiovascular outcomes: a prospective hypertensive cohort

Purpose We investigated whether blood pressure (BP) control measures, visit-to-visit BP variability, and time in therapeutic range (TTR) are associated with future cardiovascular outcomes in hypertensive patients. Materials and Methods Among 1,408 hypertensive patients without cardiovascular disease, we prospectively evaluated the incident major cardiovascular events over 6 years. In newly diagnosed patients, antihypertensive drug treatment was initiated. We estimated two markers of on-treatment BP control, (1) visit-to-visit BPV as the coefficient of variation of office systolic BP (BP-CV), and (2) TTR calculated as the percentage of office systolic BP measurements within 120–140mmHg across visits. Results The hypertensive cohort (672 males, mean age 60 years, 31% newly diagnosed) had a mean systolic/diastolic BP of 142/87 mmHg. The mean number of visits was 4.9 ± 2.6, while the mean attained systolic/diastolic BP during follow-up was 137/79 mmHg using 2.7 ± 1.1 antihypertensive drugs. The BP-CV and TTR were 9.1 ± 4.1% and 45 ± 29%, respectively, and the incidence of the composite outcome was 8.3% (n = 117). After adjustment for relevant confounders and standardization to z-scores, BP-CV and TTR were associated with a 43% (95% CI, 27–62%) increase and a 33% (95% CI, 15–47%) reduction in the outcome. However, the joint evaluation of TTR and BP-CV in a common multivariable model indicated that a standardized change of TTR was associated with the outcome to a greater extent than BP-CV (mean hazard ratios of 30% vs. 24%, respectively). When combined with the higher BP standardized-CV quartile, the lower TTR quartile predicted the outcome by 2.3 times (95% CI, 1.1–5.4) compared to the inverse TTR and BP-CV quartile pattern. Conclusion High BP-CV or low TTR was associated with future cardiovascular events in a cohort of treated hypertensive patients. As a determinant, the extent of TTR value appears greater than BP-CV when these measures are considered in the same multivariable model.

Major bleedings in mechanical prosthetic heart valves patients on Vitamin K antagonist treatment. Data from the PLECTRUM Study

Patients with mechanical prosthetic heart valves (MHV) need vitamin K antagonist (VKA) treatment, due to the high thrombotic risk. The need to evaluate the bleeding risk of these patients is of great clinical relevance. This is an observational retrospective multicenter study among Centers affiliated to the Italian Federation of Anticoagulation Clinics on MHV patients, with the aim to evaluate the risk of major bleeding (MB) and associated risk factors. 2357 patients with MHV were included in the study, patients were followed for 24.081 pt-years; 246 patients had MB (rate 1.0 ×100 pt-yrs), 54 were intracranial hemorrhage (rate 0.22 ×100 pt-yrs). Patients with MB were significantly older, more affected by peripheral obstructive arterial disease (POAD) and atrial fibrillation (AF), and presented a history of previous MB, with respect to patients who did not bleed. Patients with MB showed a trend for lower time in therapeutic range (TTR), and a significant number of patients had a TTR in the lower quartile. Patients with MB had a higher mortality rate with respect to patients who did not bleed (p=0.001). The history of previous bleeding, the presence of POAD or of AF, and a TTR in the lowest quartile, were significantly associated with MB. MHV patients treated with VKAs followed by Anticoagulation Clinics, showed a low bleeding risk. Risk factors associated with major bleeding are older age, the presence of POAD or AF, the history of previous bleeding, and poor quality of anticoagulation. Patients who experienced MB during anticoagulation are at high risk of death.

Evaluating Quality of Anticoagulation Management among Antiphospholipid Syndrome Patients: An Observational Cohort Study

Context: Vitamin K antagonists (VKA) remain the mainstay of therapy for most nonpregnant patients with thrombotic antiphospholipid syndrome (APS) considering the increased risk of thrombotic events demonstrated in prospective direct oral anticoagulants trials. Little is known, however, about the quality of anticoagulation control among VKA-treated APS patients. Aims: This study aimed to evaluate the quality of anticoagulation control in a cohort of warfarin-treated APS patients in comparison with a control group of non-APS patients. Potential predictors of anticoagulation control were also explored. Subjects and Methods: The quality of anticoagulation control (monitoring and clinical outcomes) was retrospectively evaluated in a group of APS patients and compared to a control of non-APS patients. Results: Compared to non-APS, patients with APS had a significantly lower time in therapeutic range (TTR) (64.6 ± 27.8 vs. 77.3 ± 17.8, 95% confidence interval 5.6–19.8, P ≤ 0.001). A significantly higher proportion of patients in the APS group experienced poor anticoagulation control (TTR &lt;70%) than non-APS patients (52.2% vs. 31.9%, Odds ratio 2.3 [1.4–4.1], P ≤ 0.001). APS patients were more likely to experience extreme supratherapeutic International Normalized Ratio (&gt;4.5) than their counterparts (10.9% vs. 6.1%, P &lt; 0.001). No difference in clinical events was reported. Gender was the only significant predictor of TTR among APS patients, as females experienced significantly lower TTR (Beta coefficient − 13.5, P = 0.05). Conclusions: Compared to general warfarin-treated patients with venous thromboembolism, APS patients were less likely to maintain therapeutic targets. Future studies that incorporate genetic, clinical, and social factors are recommended to fully understand the predictors of anticoagulation quality in this high-risk population.

Real-life contemporary vitamin K antagonist is still associated with very low time in therapeutic range despite strict international normalized ratio monitoring: Results of big data analysis.

This study aimed to determine the results of INR monitoring in patients on vitamin K antagonists (VKAs) and the time in therapeutic range (TTR) in 'real-world' settings. Retrospective analysis of 836,857 INR measurements performed in adults from February 2010 to August 2015 in two districts in the French Brittany region. Of the 836,857 INR measurements, 94.9% were ordered by general practitioners and 2.0% by cardiologists. The number of tests increased by 10-year age categories up to the age-group of 80-90years. The number of INR measurements increased from 169,636 in 2011 to 176,184 in 2012, but then decreased slightly to 162,597 in 2013 and 164,427 in 2014. Mean coefficient of variation of INR was 19.0%, and mean TTR was 29.0%. TTR was higher in women than in men (31% vs. 18%), in older than in younger patients (19.1% at 40years and 38.6% at 100years) and in patients with arrhythmias than in those with deep vein thrombosis/pulmonary embolism (44.4% versus 19.4%) (p<10-5 for each comparison). Median interval between INR measurements was 14days [7-28]; it was prolonged in men vs women, rural vs urban regions, older vs younger patients and when requested by GPs vs cardiologists. The interval was shorter for patients with INR outside the therapeutic range versus patients with INR within the therapeutic range (9days [5-21] vs. 18days [10-29], p<10-10 ). VKAs are still frequently prescribed in this era of direct oral anticoagulants. The low TTR cannot be explained by inadequate INR monitoring.

Switching from vitamin K antagonists to direct oral anticoagulants in non‐valvular atrial fibrillation patients: Does low time in therapeutic range affect persistence?

BackgroundNon‐valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low. ObjectiveTo examine if pre‐switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC. Patients/MethodsAdult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre‐switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100‐day prescription gap. Cumulative incidences of non‐persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre‐switch TTR levels with DOAC non‐persistence was evaluated by Cox regression models. ResultsA total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre‐switch TTR ≤ 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3–17.0%) of the patients with a pre‐switch TTR ≤ 45% became non‐persistent to DOAC within 1 year, while 9.8% (95% CI 8.7–11.0%) did in those with a pre‐switch TTR > 45%. In a multivariable model, a pre‐switch TTR ≤ 45% was associated with a higher risk of non‐persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22–1.97). Results were similar when using other cut‐off points (60% or 70%) to define a low TTR. ConclusionNVAF patients switching from VKA to DOAC due to a low pre‐switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre‐switch TTR.

Tacrolimus time in therapeutic range and long-term outcomes in heart transplant recipients.

Little is known about the association between tacrolimus time in therapeutic range (TTR) within the guideline-recommended targets and heart transplant (HT) patient outcomes. This study evaluated the association of early tacrolimus TTR with rejection and other clinical outcomes during an extended follow-up after HT. This was a single-center retrospective cohort study. The study was conducted at Michigan Medicine (1/1/2006-12/31/2017). HT recipients ≥18years of age were included. The primary end point was the effect of tacrolimus TTR on time to rejection over the entire follow-up period. A total of 137 patients were included with a median follow-up of 53months. Based on the median TTR of 58%, the patients were divided into the low tacrolimus TTR (n=68) and high tacrolimus TTR (n=69) cohort. The high tacrolimus TTR was associated with a significantly lower risk of rejection compared to the low tacrolimus TTR cohort (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41-0.98; p=0.04). A post hoc analysis revealed associations between rejection and TTR when high and low TTR groups were created at different levels. TTR <30% was associated with a 7-fold higher risk of rejection (HR 7.56; 95% CI 1.76-37.6; p<0.01) and TTR >75% was associated with a 77% lower risk of rejection (HR 0.23; 95% CI 0.08-0.627; p<0.01). Patients in the higher tacrolimus TTR cohort had a lower risk of rejection. We observed correlations between higher risk of rejection with TTR <30% and lower risk of rejection with TTR >75%. Future studies should focus on validating the optimal TTR cutoff while also exploring a cutoff to delineate high-risk patients for which early interventions to improve tacrolimus TTR may be beneficial.

Long-term adherence to direct acting oral anticoagulants and the influence of health beliefs after switching from vitamin-K antagonists: Findings from the Switching Study

AimsSwitching non-adherent patients prescribed anticoagulant treatment to a regime with less monitoring could lead to significant non-adherence. Health beliefs are known to influence medication adherence; however, the extent of this influence is unknown in patients switched from vitamin-K antagonists (VKAs) to direct oral anticoagulants (DOACs). This study aimed to determine adherence to long-term therapy in patients switched from VKAs to DOAC due to low time in therapeutic range (TTR) and if adherence is associated with health beliefs. MethodsThe Switching Study is a longitudinal observational cohort study following patients for at least 1-year. 254 patients anticoagulated with VKAs for stroke prevention in atrial fibrillation (AF) or secondary prevention of venous thromboembolism (VTE) and TTR < 50% were recruited from anticoagulation clinics at King's College Hospital, London, UK. All participants were switched to DOAC and had health beliefs measured at baseline with VKA, 1-month and 12-months after switching. ResultsOf the 220 patients who completed 12-month follow-up 39% had sub-optimal adherence measured by self-report. 23% were non-adherent according to prescriptions issued. Increasing concerns about anticoagulation over time relative to beliefs about necessity was associated with lower self-reported adherence (OR = 0.902 95%C.I: 0.836, 0.974; p = 0.008). At baseline, believing that medications in general were overused in healthcare was negatively associated with adherence to DOAC (β = −1.5, 95%C.I: −2.7, −0.3; p = 0.013). ConclusionsAlthough many patients who switched were adherent to therapy long-term, between 23 and 39% of patients exhibited sub-optimal adherence: these patients can be identified through their modifiable health beliefs at the time of switching.

Time in Therapeutic Range (TTR) and the Efficacy of Anticoagulant Therapy in Preventing Thromboembolism in Cardiac Patients Receiving Warfarin at Shifa Medical Complex: A Cross-Sectional Study

Background: Anticoagulant control is assessed by Time in Therapeutic Range (TTR). For a given patient, TTR is defined as the duration of time in which the patient’s International Normalized Ratio (INR) values were within a desired range. Aim: To assess TTR in patients receiving anticoagulant treatment and the efficacy of Anticoagulant therapy in preventing Thromboembolism in Cardiac Patients receiving Warfarin for atrial fibrillation and with high CHADS VASC score, valvular and non-valvular heart disease at a referral center for cardiovascular diseases at Gaza Shifa Medical Complex, Palestine. Materials and Method: Over 8 months, we enrolled eligible patients presenting to Shifa Medical Complex in Gaza for regular INR testing. Demographic data, medical history, and current medications were determined for all participants. TTR was assessed by both tradition and cross-sectional methods. Results: A total of 46 patients (mean age 57.15±12.6 years, 50% women) underwent 230 INR measurements. The mean TTR was calculated as 50.86±21.37%. Participants of this study were assessed for their risk of having stroke using CHADS VASC score and risk of bleeding using HAS BLED score. Risk of stroke was significantly higher for females (P= 0.031). Of the sample patients, 47.8% were in the good control category (TTR &gt;60%), and 52.2% were in the poor control category (TTR &lt;60%). The mean TTR of the studied patients (54.9%) was below the good control range.There were 12 participants had thromboembolism of patients with low traditional TTR. This was statistically significant, TTR with occurrence of thromboembolism, (P= 0.001). Conclusion: We found a mean TTR of 50.86% among study patients diagnosed with atrial fibrillation and high CHADS VASC score, valvular and non - valvular heart disease who were receiving warfarin therapy. None of the risk factor was significantly related to low TTR values among study participants. The study showed the low TTR was associated with increased risk of thromboembolism among participants in this study. Moreover, showed the superiority of tradition TTR over cross-sectional TTR in evaluating anticoagulant therapy.

Many Good Reasons to Switch from Vitamin K Antagonists to Non-Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation.

Non-vitamin K oral anticoagulants (NOACs) are the first choice for prophylaxis of cardioembolism in patients with non-valvular atrial fibrillation (AF) who are anticoagulant-naïve, as well as the preferable anticoagulation strategy in those who are on vitamin K antagonists (VKAs), but with a low time in therapeutic range (TTR). Nonetheless, there are many good reasons to consider switching from VKAs to NOACs also when TTR is >70%. From the pharmacological standpoint, anticoagulation with VKAs may remain erratic even in those patients who have high TTR values, owing to the mode of action of this drug class. Furthermore, experimental data suggest that, unlike VKAs, NOACs favorably modulate the effects of factor Xa and thrombin in the cardiovascular system through the protease-activated receptor family. Clinically, the most striking advantage provided by NOACs over VKAs, irrespective of the TTR, is the substantially lower risk of intracranial hemorrhage. NOACs have also been associated with less deterioration of renal function as compared with VKAs and may confer protection against cardiovascular events not strictly related to AF, especially the acute complications of peripheral artery disease. In this narrative review, we discuss the evidence according to which it is warranted to systematically substitute NOACs for VKAs for the prevention of AF-related stroke and systemic embolism.

Depression as a Driving Force for Low Time in Therapeutic Range and Dementia in Patients With and Without Atrial Fibrillation

Both time in therapeutic range (TTR) for anticoagulation and depression are associated with dementia risk. The purposes of this study were to examine the impact of depression on TTR and to describe the partitioned contribution of depression and TTR on long-term dementia risk. We studied 14,953 patients anticoagulated with warfarin (target INR 2-3) for atrial fibrillation (AF), venous thromboembolism (VTE), or a mechanical heart valve from 2003 to 2015. We excluded patients with a diagnosis of dementia before or within 6 months of warfarin initiation. We examined the association of depression with TTR using finite mixture modeling and logistic regression and utilized multivariable Cox hazard regression to determine the association of TTR and depression with incident dementia at 3 and 13 years. Forty % (n=6055) of patients were diagnosed with depression before or while on warfarin. Patients with depression had significantly lower TTR and were 1.37 times more likely to have TTR <50% than non-depressed patients (p <0.0001). During follow-up, 4.2% of patients received the diagnosis of dementia within 3 years as compared to 12% during all-time follow up. The 3-year risk of dementia was highest for patients with a ≤50% TTR regardless of depression status. The 3-year dementia risk was associated with TTR (p <0.0001) but not depression. However, for all-time dementia both TTR (p <0.0001) and depression (p <0.0001) as well as their interaction (p=0.049) were associated with dementia. Depression increased the risk of long-term dementia by 1.69 fold (95% CI: 1.33, 2.15) for patients with the lowest TTR. Depression is prevalent in patients managed with warfarin and is associated with significant decreases in TTR. In conclusion, decreased TTR appears to increase 3-year dementia risk and both low TTR and depression interact to increase risk for all-time dementia in patients taking warfarin.

Sex-influence on the time in therapeutic range (TTR) during oral anticoagulation with coumarin derivatives: Systematic review and meta-analysis.

We sought to investigate the association between sex and oral anticoagulation control employing coumarin derivatives. Electronic sources were MEDLINE, Biblioteca Virtual em Saúde (BVS), The Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Cochrane Central and Web of Science. Inclusion criteria were: observational and experimental studies; age ≥18 years; both sexes; treatment with any coumarin derivative for ≥3 months; any indication of long-term use; quality of oral anticoagulation measured by time in therapeutic range (TTR). The meta-analysis was developed with odds ratios (OR) for binary variables and mean differences (MD) for continuous variables, using random-effects models (DerSimonian and Laird) with 95% confidence intervals (CI). Overall, 22 articles were selected, comprising 16 cohort studies, four cross-sectional studies and two clinical trials. The number of participants ranged from 110 to 104 505 (183 612; women: 45%). The main indication of oral anticoagulation was atrial fibrillation. Most studies reported the use of warfarin. In the meta-analysis, 15 studies were analysed using TTR as a binary variable (OR = 0.87; 95% CI = 0.78, 0.96; z = -2.75; P = .006.; I2 = 67%) and seven studies as a continuous variable (MD = -2.97; 95% CI = -4.80, -1.14; z = -3.19; P = .0014; I2 = 75%). The pooled estimates indicated that women were associated with lower TTR than men. Our findings revealed an association between female sex and worse oral anticoagulation control. Further studies are needed with primary design to investigate sex-related factors influencing oral anticoagulation control with coumarin derivatives. Innovative strategies focused on women's health may be useful to improve patient-centred care.

Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal.

Background.Tacrolimus demonstrates wide intrapatient and interpatient variability requiring therapeutic drug monitoring. The utility of tacrolimus time in therapeutic range (TTR) after renal transplantation (RT) under an early corticosteroid withdrawal (ECSWD) protocol is unknown. The purpose of this study is to assess the impact of tacrolimus TTR in an ECSWD RT population.Materials.A retrospective analysis of adult RT recipients maintained on tacrolimus was conducted. Patients were excluded if they were on nonstandard protocol immunosuppression agents <12 months post-RT. Tacrolimus TTR was calculated using the Rosendaal method. Patients were divided into high (TTR-H) and low (TTR-L) TTR groups based on cohort median. The primary outcome was to compare the incidence of acute rejection 12 months post-RT. Secondary outcomes included comparing rejection subtypes, incidence of donor-specific antibody (DSA) and de novo DSA (dnDSA), risk factors for acute rejection and dnDSA development, and allograft function (serum creatinine and estimated glomerular filtration rate).Results.A total of 193 patients were analyzed (TTR-H = 98 and TTR-L = 95). There was no difference in the incidence of acute rejection (TTR-H 20.4% versus TTR-L 20.0%; P = 0.944). Positive DSA posttransplant (odds ratio [OR], 3.62; 95% confidence interval [CI], 1.41-9.26; P = 0.007) was associated with a higher acute rejection at 12 months posttransplant. Mycophenolate dose reduction (OR, 2.82; 95% CI, 1.13-6.97; P = 0.025) and acute rejection (OR, 2.99; 95% CI, 1.09-8.18; P = 0.032) were associated with dnDSA formation. No difference in serum creatinine or estimated glomerular filtration rate was observed (P > 0.05).Conclusions.Tacrolimus TTR was not significantly different with regards to acute rejection in an ECSWD population. Future studies are still needed to determine tacrolimus TTR thresholds post-RT and identify populations that may benefit from this intrapatient variability monitoring parameter.

Maximising Time in Therapeutic Range with Vitamin K Antagonists in LVAD Patients

<h3>Purpose</h3> Time in Therapeutic range (TTR) is the percentage of time an anticoagulated patient has an INR between 2-3. While studies have demonstrated a link between low TTR, bleeding and thrombosis, the mean TTR in a VAD population is between 45 and 65%. We implemented a new anticoagulation protocol using point of care devices (POC, coagucheck©), with patient education and empowerment to control their own VKA (vitamin K antagonist) dosing. <h3>Methods</h3> Before discharge all VAD patients received anticoagulation education including drug and food interaction. Depending on INR stability, patients measured INR every 2-3 days and sent a text message to the VAD team for the appropriate VKA dose. After a minimum of 2 months post VAD, if the patient and team felt comfortable, VKA dosing was delegated to the patient. Patients updated the team weekly. <h3>Results</h3> Between February and October 2020, 24 patients were included (29% HM3, 71% HW, one Bi-VAD (HW)). Median follow-up was 131 days (IQR 88-163), cumulative follow up time was 3087day or 8.5 years. Median TTR was 90% (IQR 83-97), median INR 2.41 (IQR 2.2-2.4). INR was measured 3.6 times / week (IQR 3.3-3.8). In 15 cases (62%), the VKA dosing decision was delegated to the patient. Median TTR during patient management (96%, IQR 90-97) was significantly higher than the TTR during medical control (83%, IQR 78-88) (P<0.0001). There were no deaths, major bleeding events, pump thrombosis or strokes under patient management. Ten patients (41%) received one or more doses of enoxaparin (1mg/kg once a day) as bridge for INR < 1.8 for HW and 1.6 for HM3 pump. <h3>Conclusion</h3> A TTR higher than described in the literature is achievable in VAD patients using a POC device. If prerequisites are met, VAD patients can be empowered to control their VKA dosing with excellent TTR.

Sex-based difference in anticoagulated patients with mechanical prosthetic heart valves and long-term mortality risk.

Vitamin K antagonists (VKAs) reduce thromboembolism in patients with mechanical prosthetic heart valves (MPHV). It is unclear whether a sex-based difference in MPHV patients regarding valve site, anticoagulation quality, and mortality risk does exist. We analysed 2111 MPHV patients from the nationwide PLECTRUM study promoted by the Italian Federation of Anticoagulation Clinics (FCSA). We analysed the site of MPHV, anticoagulation quality, as assessed by the time in therapeutic range (TiTR), and mortality risk in women and men. The mean age of the patients was 56.8±12.3years. Women were older with a lower prevalence of ischemic heart disease and smoking habit and a higher prevalence of atrial fibrillation at baseline. Aortic MPHV was more frequent in men (74.7% vs 43.3%, P<.001), whereas mitral (41.1% vs 17.6%, P<.001) and mitro-aortic (15.6% vs 7.7%, P<.001) MPVH in women. The association between female sex and mitral/mitro-aortic site remained at multivariable logistic regression analysis (Odds Ratio 3.623, 95% Confidence Interval [CI] 2.947-4.455, P<.001). Regarding anticoagulation quality, women showed lower mean TiTR (63.0±19.4 vs 57.5±19.2, P<.001), and a higher proportion of TiTR<60% (54.9% vs 43.3%, P<.001). During a mean follow-up of 123months (21665 pt-years), 152 deaths occurred (0.7%/year); 83 in the aortic (0.63%/year) and 69 in the mitral/mitro-aortic (0.81%/year) group. At multivariable Cox proportional hazard regression analysis, female sex was not associated with mortality (HR 0.953, 95%CI 0.678 1.340, P=.783). Female sex is independently associated with mitral/mitro-aortic MPHV. Despite a lower TiTR in women, mortality risk did not differ between the two groups.