Time Within Therapeutic Range Research Articles

Superiority of bivalirudin over heparin anticoagulation therapy for extracorporeal membrane oxygenation? Too early to draw conclusions

BackgroundWe aimed to compare the efficacy and safety of bivalirudin versus heparin as the anticoagulant in patients undergoing extracorporeal membrane oxygenation (ECMO). MethodsWe conducted a search in PubMed, Embase and the Cochrane Library for all the studies in which bivalirudin was compared to heparin as the anticoagulant for ECMO. Efficacy outcomes were defined as the time to reach therapeutic levels, time within therapeutic range (TTR), thrombotic events, circuit thrombosis, circuit exchanges. Safety outcomes were reported as heparin-induced thrombocytopenia (HIT), major bleeding events, minor bleeding events. Other outcomes included hospital length of stay (LOS), ICU LOS, mortality, 30-day mortality and in-hospital mortality. ResultsTen studies with 1091 patients were included for meta-analysis. A significant reduction in thrombotic events [OR 0.51, 95%CI 0.36,0.73, p = 0.0002, I2 = 0%], major bleeding events [OR 0.31, 95%CI 0.10,0.92, p = 0.04, I2 = 75%] and in-hospital mortality [OR 0.63, 95%CI 0.44,0.89, p = 0.009, I2 = 0%] treated with bivalirudin were found compared with heparin. There were no significant differences between groups regarding the time to reach therapeutic levels [MD 3.53, 95%CI −4.02,11.09, p = 0.36, I2 = 49%], TTR [MD 8.64, 95%CI −1.72,18.65, p = 0.10, I2 = 77%], circuit exchanges [OR 0.92, 95%CI 0.27,3.12, p = 0.90, I2 = 38%], HIT [OR 0.25, 95%CI 0.02,2.52, p = 0.24, I2 = 0%], minor bleeding events [OR 0.93, 95%CI 0.38,2.29, p = 0.87, I2 = 0%], hospital LOS [MD −2.93, 95%CI -9.01,3.15, p = 0.34, I2 = 45%], ICU LOS [MD −4.22, 95%CI -10.07,1.62, p = 0.16, I2 = 0%], mortality [OR 1.84, 95%CI 0.58,5.85, p = 0.30, I2 = 60%] and 30-day mortality [OR 0.75, 95%CI 0.38,1.48, p = 0.41, I2 = 0%]. ConclusionBivalirudin probably be a potential choice for ECMO anticoagulation. However, based on the included studies’ limitation, the superiority of bivalirudin over heparin for anticoagulation in the ECMO population still require further prospective randomized controlled studies before a definite conclusion.

Impact of a pharmacist-led tacrolimus management protocol in the outpatient setting

BackgroundClinical pharmacists are often used to make recommendations regarding tacrolimus therapy in the post transplant setting.Therapeutic drug monitoring (TDM) of tacrolimus after transplant is based on trough levels in the setting of predetermined institutional immunosuppression goals. To evaluate time within therapeutic range (TTR) of tacrolimus the Rosendaal method can be utilized. ObjectiveOur study aimed to compare objective therapeutic drug monitoring outcomes after the implementation of a pharmacist driven tacrolimus management protocol (postprotocol initiation) with previous management by providers (preprotocol initiation). Practice descriptionThe Ohio State University Wexner Medical Center (OSUWMC) is a 700-bed academic medical center in Columbus, OH. On average, OSUWMC completes more than 300 kidney transplants each year. There are 6 abdominal transplant pharmacists (including one postgraduate year 2 transplant pharmacy resident) that rotate through the inpatient and outpatient setting. Practice innovationA pharmacist-led tacrolimus management protocol in kidney transplant recipients was initiated in October 2018 at our institution, which enabled pharmacists to dose and adjust tacrolimus in the outpatient setting in accordance with prespecified goals. Evaluation methodsThis single-center retrospective analysis included adult kidney transplant recipients on de novo tacrolimus. Patient’s tacrolimus levels were evaluated for 6 months after transplant. The mean tacrolimus percent TTR and the median coefficient of variation (CV) were calculated and compared in postprotocol initiation group (n = 85) with preprotocol initiation group (n = 39). TTR was calculated using the Rosendaal method. ResultsThere was no statistically significant difference between the preprotocol initiation and postprotocol initiation group mean TTR (59.6% vs. 60.5%, P = 0.723), mean CV from 0-3 months after transplant (36.3 vs. 36.0, P = 0.900), and mean CV from at least 3-6 months after transplant (24.5 vs. 22.7, P = 0.351). Rejection rates, development of donor-specific antibodies, and renal function were similar between groups. ConclusionBased on our findings, transplant pharmacists were equally as effective at maintaining tacrolimus percent TTR and CV in the designated kidney transplant recipients included in the management protocol compared with primary management by other transplant providers. The delegation of tacrolimus management to clinical pharmacists is a viable alternative to primary management by outpatient practitioners.

Time to Therapeutic Tacrolimus Levels and Association with Acute Cellular Rejection and De Novo Donor-Specific Antibody Development in Lung Transplant Recipients

<h3>Purpose</h3> Tacrolimus (FK506) is standard of care for preventing rejection in lung transplant (LTx) for maintenance immunosuppression. Both acute cellular rejection (ACR) and <i>de novo</i> donor-specific antibodies (dnDSAs) are strongly associated with development of chronic lung allograft dysfunction. Time to therapeutic FK506 has not been standardized. We evaluated whether time to therapeutic FK506 impacted ACR and <i>dn</i>DSA rates within 6 months (M) of LTx. <h3>Methods</h3> We reviewed LTx recipients between 5/2016 - 12/2019. We excluded patients who did not receive FK506, received their first dose ≥48 hours post-LTx, were transitioned off FK506 during the study period, or expired within 30 days (d). Primary outcome was a composite of ACR and <i>dn</i>DSA development within 6M for patients achieving therapeutic FK506 (8-15 ng/mL) within 7d, versus >7d. Secondary endpoints included: time within therapeutic range (TTR) at 1M and incidence of acute kidney injury (AKI) within 14d. <h3>Results</h3> Median time to therapeutic was 7d (IQR 5.0-10.0) in 222 patients. There was no difference in ACR [7.6% vs 9.7% (p=0.63)] or dnDSA [35% vs 44% (p=0.20)] between patients achieving therapeutic FK506 ≤7d vs >7d. Recipients therapeutic ≤7d had a longer median time to dnDSA development (44d vs 27d, p=0.043). TTR at 1M was longer in patients therapeutic ≤7d (40% vs 28%, p<0.001). Neither median nor percentage of TTR had an impact on the composite outcome (HR 0.99; 95% CI 0.95-1.03). AKI incidence (≥stage 2) was similar (40.3% vs 38.8%, p=0.82) between groups. Multivariate analysis identified receipt of a double LTx as the only covariate associated with a higher risk of AKI [OR 3.56, 95% CI 1.40-9.05 (p=0.01)]. <h3>Conclusion</h3> There was no significant differences in development of ACR or dnDSA within 6M between LTx recipients achieving therapeutic FK506 ≤7d vs >7d. Increased time to dnDSA development in the ≤7d cohort suggests a potential benefit to minimizing time to therapeutic FK506 level post-LTx.

Quality of anticoagulant therapy and the incidence of in‐stent thrombosis after venous stenting

BackgroundIn patients with a venous outflow obstruction following iliofemoral deep vein thrombosis stenting of the venous tract to prevent or alleviate postthrombotic syndrome is applied with increasing frequency. The impact of the quality of anticoagulant therapy with vitamin K antagonists (VKAs) on the development of in‐stent thrombosis is currently unknown. ObjectivesTo determine the association between the quality of postinterventional VKA treatment and the occurrence of in‐stent thrombosis. MethodsSeventy‐nine patients with iliofemoral and/or caval venous stent placement for obstruction of the venous outflow were included in this study. All patients received postinterventional VKA. The quality of VKA anticoagulant therapy was expressed as the time within therapeutic range (TTR) calculated using the linear interpolation method and as the proportion of International Normalized Ratio (INR) values < 2.0. In‐stent thrombosis was assessed by the use of duplex ultrasound. Survival analysis (Kaplan‐Meier curves, Cox regression) was used to analyze the data. ResultsIn‐stent thrombosis developed in 16 patients (20.3%). The total population had a mean TTR of 64.0% (±19.0) and a mean proportion of INR values < 2.0 of 11.6% (±12.0). Overall, a TTR < 49.9% was associated with an increased risk of in‐stent thrombosis. The multivariable adjusted analysis showed a hazard ratio (HR) of 0.96 (95% confidence interval [CI], 0.92‐0.99; P = .02) per 1% increase in TTR. The proportion of INR values < 2.0 had no significant association with the occurrence of in‐stent thrombosis: HR 0.98 (95% CI, 0.91‐1.06; P = .66). ConclusionsWe conclude that the quality of anticoagulant treatment reflected in the TTR following a venous stenting procedure is an important independent determinant for the risk of in‐stent thrombosis. The role of anticoagulant treatment for the prevention of in‐stent thrombosis following stenting procedures therefore merits further research.

The Effect of Warfarin Administration Time on Anticoagulation Stability (INRange): A Pragmatic Randomized Controlled Trial.

Without supporting evidence, clinicians commonly recommend that warfarin be taken in the evening. We conducted a randomized controlled trial to evaluate the effect of administration time (morning vs evening) on the stability of warfarin's anticoagulant effect. A total of 236 primary care physicians serving 54 western Canadian communities mailed letters of invitation to all their warfarin-using patients. Eligible patients were community-dwelling warfarin users (any indication) with at least 3 months of evening warfarin use and no plans for discontinuation. Participants were randomized (by web-based allocation) to morning vs continued evening warfarin ingestion. We used the Rosendaal method to determine the proportion of time within therapeutic range (TTR) of the international normalized ratio (INR) blood test month 2 to 7 postrandomization vs the 6 months prerandomization. The primary outcome was the percent change in proportion of time outside target INR range (with an a priori minimum clinically important difference of ±20%). All analyses were intention to treat. Between March 8, 2015 and September 30, 2016, we randomized 109 participants to morning and 108 to evening warfarin use. TTR rose from 71.8% to 74.7% in the morning group, and from 72.6% to 75.6% in the evening group, for a change in TTR of 2.9% in the former vs 3.0% in the latter (difference, -0.1%; P = .97; 95% CI for the difference, -6.1% to 5.9%). The difference in percent change in proportion of time outside the therapeutic INR range (obtained via Hodges-Lehmann estimation of the difference in medians) was 4.4% (P = .62; 95% CI for the difference, -17.6% to 27.3%). Administration time has no statistically significant nor clinically important impact on the stability of warfarin's anticoagulant effect. Patients should take warfarin whenever regular compliance would be easiest.

Providers' utilization and perceptions of warfarin dosing algorithms

IntroductionWarfarin dosing algorithms have proven beneficial in increasing time within therapeutic range (TTR) and decreasing adverse events associated with out-of-range international normalized ratios (INRs). Despite widespread availability, providers' utilization and perceptions of warfarin algorithms in real-world practice are unclear. Identifying perceptions and barriers to algorithm use may help attempts to improve warfarin therapy management. MethodsAnticoagulation providers' utilization and perceptions of warfarin dosing algorithms were assessed via a nationwide electronic survey. ResultsOf the 246 providers who completed the survey, 82% were pharmacists, and 69% had over five years' experience dosing warfarin. Warfarin dosing algorithms were deemed beneficial by 84% of respondents and 72% currently use a warfarin dosing algorithm in their practice at least occasionally. Pharmacists were least likely of anticoagulation providers to use algorithms, although this was not statistically significant (p = 0.12). Algorithm utilization also decreased as years of warfarin dosing experience increased, with the highest rate of usage noted in the first year of dosing warfarin. The most common reason providers gave for discontinuing algorithm use was that they no longer felt it was needed. In this study, clinic patient volume did not appear to be associated with algorithm utilization. ConclusionWarfarin dosing algorithms are frequently used among anticoagulation providers, especially those new to dosing warfarin, but use is frequently not sustained over the long-term. Education on the continued benefits of warfarin dosing algorithms could increase long-term utilization, potentially improving patient outcomes.

Long-term effectiveness and safety of self-management of oral anticoagulants in real-world settings

BackgroundThe patient self-management (PSM) is an effective approach for controlling the international normalized ratio, INR, within the therapeutic range. Nevertheless, most of the literature derives from randomized clinical trials, and no from routine clinical practice. The main objective of the present study was to evaluate long-term effectiveness and safety of PSM of oral anticoagulants (OACs) in real-world settings.MethodsThis prospective cohort study involved 808 patients who were trained for PSM between July 2009 and March 2012, and followed-up for a maximum observational period of 5 years. The follow-up consisted of a visit to the physician every 6 months. All patients used the same type of portable coagulometer, able to store digitally up to 100 INR measurements. Effectiveness outcomes included the percentage of patients within the therapeutic range, the time within therapeutic range (TTR), and the evolution of the TTR over 365 days of follow-up. Long-term safety profile of PSM included the incidence of all-cause deaths and complications (thromboembolic or hemorrhagic) reported between July 2009 and June 2014, and the time to event.ResultsThe median follow-up was 3.3 years. The percentage of patients within therapeutic INR target range was 67.5%. The median TTR was 71.5%. The TTR increased over the follow-up period, either overall and regarding target INR. All-cause mortality was 2.4 per 100 patient-years (59 cases). The thromboembolic event rate was 0.9 per 100 patient-years (24 cases). The rate of major hemorrhages was 0.45 per 100 patient-years. Patients who drop out the PSM to perform the conventional management had greater rates of complications: 2.4, 1.8, and 3.4 per 100 patient-years for thromboembolic complications, major hemorrhagic events, and mortality, respectively.ConclusionsThe PSM of OACs is effective for maintaining patients within the INR therapeutic range for a long period of time in routine clinical practice. Results of the present study suggest that its effectiveness is at least comparable to the conventional management. Moreover, it seems safe in real-world settings, by preventing all-cause mortality, and thromboembolic and major hemorrhagic complications.Trial registrationThis study was not a trial, thus registration was not required.

Time in Therapeutic Tacrolimus Range Predicts 1-Year Clinical Rejection and Survival: Time For a Paradigm Shift?

Purpose Calcineurin inhibitors are a cornerstone of immunosuppression post-orthotopic heart transplantation (OHT). The relationship of tacrolimus exposure, measured by time within therapeutic range (TTR), and level variability, measured by standard deviation (SD) of trough blood levels, to post-OHT acute rejection is unclear. We evaluated if tacrolimus TTR or variability in the 1-year post OHT impacted rejection. Methods This was a single-center, retrospective cohort study of consecutive adult OHT patients receiving standard immunosuppression with tacrolimus, MMF, and prednisone. Tacrolimus TTR was calculated up to 1 year using protocol goal ranges (10-15 ng/mL for months 0-2, 8-12 ng/mL for months 2-6 and 5-10 ng/mL for months 6-12) using the Rosendaal method. The primary outcomes included the association of TTR and level variability with 1-year clinical rejection (defined as any patient receiving ≥ 125 mg of IV methylprednisolone from post-op day 7-365). We analyzed categorical and continuous variables using chi-square and Mann Whitney-U respectively. Time-to-event analysis was conducted for 1-yr clinical rejection using both Kaplan-Meier and Cox Proportional Hazards methods, whereby TTR was calculated until event or censor date and reported using hazard ratio (HR) and 95% confidence interval (CI). Results 78 patients underwent OHT (age, 56.2 ± 12.7 years) with a median 1-yr TTR of 50.2%. Clinical rejection occurred in 31 (39.7%) patients. Those with clinical rejection had a significantly lower median TTR (45.9%) and higher level variability (5.8) than those without rejection (TTR 56.5%, variability 4.9; p=0.021 and p=0.005, respectively) (Figure A&B) . Time to therapeutic tacrolimus level (median 9 days) did not predict 1-year clinical rejection (p=0.274). In a univariable Cox Proportional Hazards Model (median TTR=40%), TTR Figure C ). Five (6.4%) patients died in the first year after OHT. TTR 50% (p=0.018, Figure D ). Conclusions Lower tacrolimus TTR and/or greater level variability predicts clinical rejection and death in the first year after OHT. TTR and and level variability should be monitored in addition absolute levels.

Questioning the Tacrolimus Dogma: Does Early Dose Control Matter?

Tacrolimus is the mainstay of immunosuppressive strategies post orthotopic heart transplantation (OHT). The relationship of tacrolimus control, measured by time to therapeutic trough (TTT) or time within therapeutic range (TTR) to post-OHT acute rejection is unclear. We evaluated if tacrolimus TTT or TTR in the 30 days post OHT impacts rejection.

Factors Affecting the Quality of Anticoagulation With Vitamin K Antagonists in Venous Thromboembolism Patients.

Treatment of venous thromboembolism (VTE) is classically based on oral vitamin K antagonists (VKAs). Due to the disadvantages and side effects of these drugs, monitoring the quality of anticoagulation by assessing time within therapeutic range (TTR) is recommended. Variables altering the TTR in patients with VTE are yet to be determined. The aim of this study was to analyze the quality of anticoagulation in patients with VTE treated with VKAs and to identify factors associated with poor-quality anticoagulation. A retrospective observational study was performed in a cohort of 94 patients diagnosed with VTE undergoing treatment with VKAs. The TTR at 6 months was analyzed by the Rosendaal method. Univariate and a multivariate logistic regression analyses were performed to unravel factors that increase risk of poor-quality anticoagulation. The TTR at 6 months in this cohort was 60.5%; 54 patients had a TTR < 65%. In the univariate analysis, female sex, age ≥ 65 years, and renal impairment were significantly associated with poor-quality anticoagulation. However, in the multivariate logistic regression model, only renal impairment was independently associated with poor-quality anticoagulation (odds ratio = 3.31, 95% confidence interval [1.049, 10.486], p = .041). The average quality of anticoagulation was 60.5%, and a high percentage of patients had a quality of anticoagulation below recommended levels. Study findings indicate that renal impairment is an independent risk factor for poor-quality anticoagulation in patients with VTE treated with VKAs.

Impact of a Guideline for the Management of Antimicrobial/Warfarin Interactions in the Inpatient Setting and Across Transition of Care

Drug-drug interactions (DDIs) with warfarin and antimicrobial agents are a common cause of international normalized ratio (INR) instability, which can affect the risk for bleeding and thrombotic events. The purpose of this study was to assess the impact of a comprehensive guideline for the management of warfarin-antimicrobial DDIs across transitions of care. The guideline emphasizes improving identification of significant antimicrobial-warfarin DDIs during hospitalization, empirical warfarin dose modification based on DDI and baseline INR, patient education, documentation of the DDI, communication with outpatient providers regarding the DDI and anticipated antimicrobial stop date, and warfarin dose adjustment on discontinuation of antimicrobial. This retrospective, single-center, quasiexperimental, pre-post study compared end points 3 months before and after guideline implementation. The primary outcome was time within therapeutic range (TTR). The study included 78 preguideline and 31 postguideline patients; baseline characteristics were similar between groups. Implementation of the guideline resulted in greater in-hospital TTR (72% vs 50%, P = 0.04) and improved TTR across transition of care (70% vs 46%, P = 0.01). Documentation of DDI in the pharmacy anticoagulation discharge summary significantly improved in the postguideline group (40% vs 14%, P = 0.02) and numerically improved within the daily pharmacy progress notes (94% vs 82%, P = 0.13). The implementation of the guideline was associated with a nonsignificant, numerical reduction in bleeding events compared with the preguideline group (0 vs 4 events, P = 0.11). This single-center approach to optimize the comprehensive management of significant antimicrobial-warfarin DDIs resulted in improved communication with outpatient providers and improved INR TTR.

Assessment of psychometric properties of the Brazilian version of the oral anticoagulation knowledge test.

BackgroundThe aim of this study was to evaluate the psychometric properties of the Brazilian version of the Oral Anticoagulation Knowledge (OAK) Test.MethodsThis study, conducted in an anticoagulation clinic, included 201 Brazilian participants aged over 18 years, who had been using warfarin for more than two months. The reliability of the instrument was evaluated by assessing internal consistency (Kuder-Richardson coefficient) and reproducibility (test-retest reliability). The validity was evaluated by hypothesizing that there would be a positive correlation of moderate to strong intensity between the correctness levels of the OAK Test and time within therapeutic range (TTR) values, which is a measure used to evaluate the quality of oral anticoagulation.ResultsThe instrument exhibited good psychometric properties. The total a Kuder-Richardson coefficient value was 0.818 and intraclass correlation coefficient was 0.967. The validity revealed a strong positive correlation between the values of the level of knowledge, as measured by the OAK Test and the TTR values (rs = 0.780).ConclusionThe instrument proved to be a reliable and valid tool for evaluating the knowledge of Brazilian patients on oral anticoagulation therapy with warfarin. This instrument may be incorporated into the practice of health care for substantiating the structuring of educational activities to ensure the improvement of knowledge about the use of warfarin, thereby increasing the effectiveness and safety of treatment.

P44 Anticoagulation control in adults with congenital heart disease

Background Among patients with acquired cardiovascular disease taking oral vitamin K antagonist medications, time within therapeutic range (TTR) is considered poor when below 60%. To date, however, there are no data about anticoagulation control in adults with congenital heart disease (CHD). This is concerning given that they represent an emerging and growing population of cardiac patients with specific management considerations. Objectives In a sample of adults with CHD taking oral vitamin K antagonist medications, we investigated (i) TTR and (ii) socio-demographic and medical factors associated with lower anticoagulation control. Methods In this retrospective study, the following were study inclusion criteria: age ≥ 18 years, diagnosis of CHD, prescribed oral vitamin K antagonist medication, followed in the thrombosis clinic at least once between January 2005 and December 2010, and adequate frequency of recording of INR values. We documented medical and socio-demographic background, indication for anticoagulation therapy, international normalised ratio (INR) values, and TTR; data were recorded through December 2013. Results We identified 119 eligible patients (49% male; mean age = 39 ± 17 years; mean follow up duration = 4 ± 2.3 years). Defect complexity was categorised as simple (n = 29; 24%), moderate (n = 46, 39%) or great (n = 44; 37%). Specific indications for oral anticoagulation were cardiac arrhythmias (n = 60; 51%), prior thrombus/emboli event (n = 30; 25%), mechanical valves (n = 24; 20%), and other (n = 5; 4%). Twenty-three patients (19%) had a documented psychiatric disorder and 21 patients (18%) had a history of medication non-adherence. Of 71 patients with known educational attainment, 45 (38%) had earned college or university degrees. Of 119 study patients, the mean TTR was 49 ± 19% (range: 0–89%); 82 patients (69%) had poor anticoagulation control (TTR Conclusions Among our study cohort of adults with CHD, patients were within therapeutic INR range only half of the time and more than two-thirds of patients had poor anticoagulation control. Poorer anticoagulation control was observed in patients with moderate defect complexity, with mechanical valves, and with a documented history of medication non-adherence. Future investigation into the clinical outcomes of sub-optimal INR control as well as the potential role of novel oral anticoagulant agents is encouraged.

Quality of anticoagulation control among patients with atrial fibrillation: An experience of a tertiary care center in Saudi Arabia

BackgroundAtrial fibrillation (AF) is the most common chronic rhythm disorder. Patients with AF are at an increased risk of ischemic stroke. Therefore, optimal anticoagulation is essential to reduce the risk of stroke. The aim of this study was to assess the level of anticoagulation control achieved in patients with nonvalvular AF receiving medical care in a tertiary care hospital. MethodsThis was a retrospective cohort study in ambulatory care clinics at tertiary care hospital in Saudi Arabia. We included 110 nonvalvular AF patients treated with warfarin for at least 3months at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between May 1, 2012, and July 31, 2012. Thereafter, international normalized ratio results were collected for 1year. Anticoagulation control was assessed by calculating time within therapeutic range (TTR) as per the Rosendaal method. ResultsThe mean age was 64.9±16.5years; 60.9% were female. The mean TTR was 59%. Almost one third of the patients (32.7%) had poor anticoagulation control; TTR of <50%. Poor anticoagulation control was significantly associated with higher CHADS2 (congestive heart failure, hypertension, age, diabetes, stroke) score (p=0.043). TTR was not significantly different between men and women. Similarly, TTR was not associated with age or duration of anticoagulation. There was no adequate information to assess the effect of other factors such as diet, compliance, and level of education on anticoagulation. Thirty-one patients (28.2%) had a history of prior stroke. The overall quality of anticoagulation was not significantly different between patients with and without stroke, (TTR was 56.3% and 60.1%, respectively; p=0.46). ConclusionQuality of anticoagulation in patients with AF receiving medical care in a tertiary care hospital was suboptimal, with nearly 40% of the time spent outside the therapeutic range. Methods to improve anticoagulation control among patients with AF should be implemented.

Effect of distance to health facility on the maintenance of INR therapeutic ranges in rheumatic heart disease patients from Cape Town: no evidence for an association

BackgroundLack of adherence to international normalised ratio (INR) monitoring in rheumatic heart disease (RHD) patients is a contributor to cardio-embolic complications. This population-based observational study investigated whether the distance between home and an INR clinic affects the maintenance of therapeutic INR in RHD patients on warfarin.MethodsResidential addresses, INR clinics, and INR results of patients with RHD were extracted from the Cape Town component of the Global Rheumatic Heart Disease Registry (REMEDY) database. Addresses of homes and INR clinics were converted to geographical coordinates and verified in ArcGIS 10®. ArcGIS 10® and Google Maps® were used for spatial mapping and obtaining shortest road distances respectively. The travel distance between the home and INR clinic was correlated with time within therapeutic range (TTR) using the Rosendaal linear interpolation method, and with the fraction of INR within range, based on an average of three INR readings of patients and compared with recommended therapeutic ranges.ResultsRHD patients (n = 133) resided between 0.2 km and 50.8 km (median distance, 3.60 km) from one of 33 INR clinics. There was no significant difference in the achievement of the therapeutic INR between patients who travelled a shorter distance compared to those who travelled a longer distance (in range = 3.50 km versus out of range = 3.75 km, p = 0.78). This finding was the same for patients with mechanical valve replacement (n = 105) (3.50 km versus 3.90 km, p = 0.81), and native valves (3.45 km versus 2.75 km, p = 0.84).ConclusionsThere is no association between the maintenance of INR within therapeutic range amongst RHD patients in Cape Town and distance from patients’ residence to the INR clinic.

Fasting and warfarin

Recently, we reported the findings of a study on the effects of Ramadan fasting on a group of 32 Muslim patients taking warfarin.13 Weekly INR (international normalized ratio) readings were taken from subjects with previously stable INRs over a three-month period spanning pre-Ramadan to post-Ramadan. We found a statistically significant increase in the mean INR by 0.23 (p=0.006) during Ramadan from the pre-Ramadan month and decreased by 0.28 (p<0.001) after Ramadan. There was no significant difference (p=1.000) in mean INR between the non-Ramadan months. Importantly, there was a decline in the time within therapeutic range (TTR) during Ramadan with a corresponding increase in TTR above the therapeutic target range. %TTR declined from 80.99% before Ramadan to 69.56% during Ramadan (p=0.453). The first out-of-range INR was seen around 12.1 days (95% CI 9.0-15.1) after the start of fasting and returned within range about 10.8 days (95% CI 7.9-13.7) after Ramadan. Time above range increased from 10.80% pre-Ramadan to 29.87% during Ramadan (p=0.027), while time below range increased from 0.57% during Ramadan to 15.49% post-Ramadan (p=0.006). This observation is directly attributable to the effects of fasting.

Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation

Bleeding risk (often perceived, rather than actual) is a common reason for cessation of oral anticoagulation with Vitamin K antagonists (VKA). We investigate clinical outcomes in a consecutive population of VKA naïve atrial fibrillation (AF) patients, who initiated VKA therapy in our clinic. We included consecutive VKA-naïve patients with non valvular AF, initiated on VKA therapy in our anticoagulation outpatient clinic in 2009. During follow-up, adverse events [thrombotic/vascular events (stroke, acute coronary syndrome, acute heart failure and cardiac death), major bleeding and death], and VKA cessation were recorded. At the end of the follow-up, we determined time within therapeutic range (TTR), using a linear approximation (Rosendaal method). We studied 529 patients (49% male, median age 76), median follow-up 835 days (IQR 719-954). During this period 114 patients stopped VKA treatment. 63 patients suffered a thrombotic/cardiovascular event (5.17%/year, 27 thrombotic/ischaemic strokes), 51 major bleeding (4.19%/year) and 48 died (3.94%/year). Median TTR was 54% (34-57). On multivariate analysis (adjusted by CHA₂DS₂-VASc score), VKA cessation was associated with death [Hazard Ratio (HR) 3.43; p<0.001], stroke [4.21; p=0.001] and thrombotic/cardiovascular events [2.72; p<0.001]. Independent risk factors for major bleeding were age [1.08; p<0.001], previous stroke [1.85; p=0.049], and TTR [0.97; p=0.001], but not VKA cessation. In conclusion, in AF patients AF, VKA cessation is independently associated with mortality stroke and cardiovascular events. Specifically, VKA cessation independently increased the risk of stroke, even after adjusting for CHA₂DS₂-VASc score. TTR was an independent risk factor for major bleeding following initiation of VKA therapy.

Potential benefits of warfarin monitoring by a clinical pharmacist in a long term care facility

The primary objective of this study was to determine whether warfarin therapy monitoring by a pharmacist would benefit a long-term care facility, by maintaining patients within therapeutic INR range more consistently than the current practice of physician monitoring.Secondary objectives included whether adverse events resulting from non-therapeutic INR levels differed significantly between groups and whether pharmacist interventions resulted in decreased overall costs to the facility. A retrospective chart review was conducted on all patients treated with warfarin for a minimum of 14 days within a Long-Term Care (LTC) facility to compare Time within Therapeutic Range (TTR) between staff treated patients versus pharmacist treated patients. A total of 552 INRs were obtained for all patients during the study period: 499 (90.4%) under staff supervision and 53 (9.6%) under clinical pharmacist supervision. Of the 499 tests performed by the River Garden staff, 203 were within the desired range, compared with 29 of the 53 tests performed by the clinical pharmacist being in range. For the primary endpoint, a total of 1483 INRs were imputed, corresponding to the number of days between true INR measurements. INRs attributable to clinic staff management were within the therapeutic range 47.1% of the time, whereas INRs attributable to clinical pharmacist management were within the therapeutic range 58.7% of the time (P < 0.0001 for the comparison). Warfarin can be effectively monitored by a clinical pharmacist and routinely lead to appropriate INR levels in the nursing home setting, while potentially saving the facility healthcare dollars.

Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients

Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.