INR variability in atrial fibrillation: A risk model for cerebrovascular events

BackgroundUse of vitamin K antagonists (VKAs) for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) necessitates frequent monitoring of the international normalized ratio (INR) to avoid the increased risk of hemorrhage associated with excess anticoagulation, or ischemic stroke due to insufficient anticoagulation. We therefore developed a model to estimate the excess morbidity attributable to inadequate INR control in NVAF populations.MethodsEquations expressing the risk of cerebrovascular events as a function of INR were generated using published data. Additional functions were developed to estimate the excess risk attributable to inferior INR control, using the clinical trial setting as the reference.ResultsThe derived risk functions were applied to French NVAF patients receiving anticoagulation in routine medical practice. This population achieved a time in therapeutic range (INR 2.0–3.0) of 59%, compared with 68% time in therapeutic range (TTR) in the SPORTIF III and V clinical trials. However, there was considerable variation in the TTR among patients in routine care, of whom 36% were in range for less than 50% of the time. Among this latter group, the relative risk, compared with the clinical trial setting, was 1.47 for ischemic stroke and 2.68 for intracranial hemorrhage. Conversely, for patients achieving a TTR greater than 50%, the relative risks for ischemic stroke and intracranial hemorrhage were 0.99 and 1.16, respectively.ConclusionsThis model permits estimation of the excess risk attributable to inferior INR control in NVAF populations receiving VKA anticoagulation, and has implications for public health planning and management.     

Les cliniques d’anticoagulants sont-elles efficaces en France ? Évaluation des performances de six cliniques dans la gestion des traitements par antivitamines K

Purpose

Recent data show that the quality of anticoagulation evaluated in patients receiving vitamin K antagonists (VKA) is not optimal in France. The aim of this retrospective study was to estimate the performances of six French anticoagulant clinics that manage VKA treatments over a 3-year period, from 2009 to 2011.

Methods

All clinics used the same rule based software. We determined the time spent in the therapeutic range (TTR), a surrogate end-point of quality of treatment with VKA.

Results

The overall duration of follow-up was 2755 patient-years concerning 2385 patients. The time spent in the therapeutic range 2 to 3 assigned for 89% of the patients, was 73%. On the other hand the time spent in the therapeutic range for the other two INR ranges (2.5–3.5 and 3–4.5) concerning 11% of patients with prosthetic heart valve was lower (63.7% and 68.8% respectively) with an imbalance in favour of the time below the range. In this study, warfarin (Coumadine^®) and fluindione (Previscan^®) allowed an equivalent quality of anticoagulation. The 1728 patients of age ranged from 60 to 100 years spent more time in TTR than the 651 younger patients. The percentage of time spent with an INR greater than 5 was extremely reduced which is a guarantee of safety.

Conclusion

These results prove that anticoagulant clinics in France have the same good performances as their counterparts abroad. It can be assumed that a high TTR contributes to a low incidence of both bleedings and thrombosis.     

Razón internacional normalizada y mortalidad de los pacientes con insuficiencia cardiaca y fibrilación auricular tratados con antagonistas de la vitamina K

Introduction and objectivesHeart failure patients with nonvalvular atrial fibrillation (NVAF) on treatment with vitamin K antagonists (VKA) often have suboptimal international normalized ratio (INR) values. Our aim was to evaluate the association between INR values at admission due to acute heart failure and mortality risk during follow-up.MethodsIn this observational study, we retrospectively assessed INR on admission in 1137 consecutive patients with acute heart failure and NVAF who were receiving VKA treatment. INR was categorized into optimal values (INR = 2-3, n = 210), subtherapeutic (INR < 2, n = 660), and supratherapeutic (INR > 3, n = 267). Because INR did not meet the proportional hazards assumption for mortality, restricted mean survival time differences were used to evaluate the association among INR categories and the risk of all-cause mortality.ResultsDuring a median [interquartile range] follow-up of 2.15 years [0.71-4.29], 495 (43.5%) patients died. On multivariable analysis, both patients with subtherapeutic and supratherapeutic INR showed higher risks of all-cause mortality, as evidenced by their restricted mean survival time differences at 5 years’ follow-up: –0.50; 95%CI, –0.77 to –0.23 years; P < .001; and –0.40; 95%CI, –0.70 to –0.11 years; P = .007, respectively, compared with INR 2-3.ConclusionsIn acute heart failure patients on treatment with VKA for NVAF, INR values out of normal range at admission were independently associated with a higher long-term mortality risk.     

Bridging for an isolated subtherapeutic INR: an evaluation of clinical practice patterns, outcomes, and costs from an anticoagulation clinic

No formal recommendations support bridging patients taking warfarin for a subtherapeutic international normalized ratio (INR). This study aimed to: (1) characterize practices at one anticoagulation clinic, (2) evaluate adverse events, and (3) compare cost of bridging versus withholding bridging for subtherapeutic INR. A retrospective chart review of 320 patients having 546 isolated subtherapeutic INR episodes included patients with an INR below their therapeutic range, preceded by two INRs within or above range. Bridged episodes required more frequent follow-up visits to achieve therapeutic INR (2.5 ± 1.0 vs. 2.2 ± 0.6; P = 0.097), but fewer days until the INR returned to therapeutic range (6.8 ± 5.0 vs. 18.9 ± 16.0; P < 0.0001). The strongest predictor of bridging was the magnitude the INR fell below the therapeutic range, where those with a severely-low INR were 30-fold more likely to be bridged (P < 0.0001), and moderately-low INR episodes were 6-fold more likely to be bridged compared with mildly-low INR (P < 0.0001). Those at high thromboembolic risk were more likely to be bridged than at low-risk (OR 3.39 [1.50–7.68]; P = 0.0034). Increasing age reduced the likelihood of being bridged (OR 0.97 [0.95–0.99]; P = 0.0118). Adverse events were infrequent in both the bridged and non-bridged; thrombosis (2.0 vs. 0.7%), major bleeding (2.0 vs. 1.3%), minor bleeding (4.1 vs. 3.1%) and bruising (18.4 vs. 3.6%). Incremental cost difference of bridging was significantly greater for total cost (967.13) and its components, direct medical (967.13) and its components, direct medical (951.32), transportation (2.73) and productivity cost (2.73) and productivity cost (13.08). It is unclear if bridging for an isolated subtherapeutic INR reduces thrombosis risk, but it is associated with higher costs.     

Improving Warfarin Management Within the Medical Home: A Health-System Approach

Background

Anticoagulation clinics have been considered the optimal strategy for warfarin management with demonstrated improved patient outcomes through increased time in therapeutic international normalized ratio (INR) range, decreased critical INR values, and decreased anticoagulation-related adverse events. However, not all health systems are able to support a specialized anticoagulation clinic or may see patient volume exceed available anticoagulation clinic resources. The purpose of this study was to utilize an anticoagulation clinic model to standardize warfarin management in a primary care clinic setting.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

In this study, we investigated the contribution of vitamin K epoxide reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotypes, age, and body surface area (BSA) on warfarin dose requirements and in an adult Turkish population. Blood samples were collected from 100 Turkish patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the therapeutic range. Genetic analyses for CYP2C9 genotypes (*2 and *3 alleles) and VKORC1 −1639 G>A polymorphism were performed and venous INR determined. The mean warfarin daily dose requirement was higher in CYP2C9 homozygous wild-type patients, compared to those with the variant *3 allele (P < 0.05), similar to those with the variant *2 allele (P > 0.05) and highest in patients with the VKORC1 −1639 GG genotype compared to those with the GA genotype and the AA genotype (P < 0.01). The time to therapeutic INR was longer in CYP2C9 homozygous wild-type patients compared with those with the variant *2 and *3 alleles (P < 0.01), and longer in patients with the VKORC1 (position −1639) GG genotype compared with those with the GA genotype and the AA genotype (P < 0.01). The multivariate regression model including the variables of age (R ² = 4.4%), BSA (R ² = 27.4%), CYP2C9 (R ² = 8.1%), and VKORC1 genotype (R ² = 34.1%) produced the best model for estimating warfarin dose (R ² = 60.4%). VKORC1 genotype and CYP2C9 polymorphism affect daily dose requirements and time to therapeutic INR in Turkish patients receiving warfarin for anticoagulation.     

Influence of proton pump inhibitors and VKORC1 mutations on CYP2C9‐mediated dose requirements of vitamin K antagonist therapy: a pilot study

Interindividual variations in dose requirements of oral vitamin K antagonists (VKA) are attributed to several factors, including genetic variant alleles of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9), but also interaction with co‐medications. In this context, proton pump inhibitor (PPI)‐related alterations of VKA maintenance dose requirements have been published. The present investigation aimed to test for an interaction profile of oral VKA‐therapy and PPIs in relation to the CYP2C9 genotype. Median weekly stable VKA dose requirements over 1 year were recorded in 69 patients. Patients were genotyped for CYP2C9*2, CYP2C9*3, VKORC1c.‐1639G>A and VKORC1c.174‐136C>T and assessed for an association with PPI use and total VKA maintenance dose requirements. PPI users with CYP2C9 genetic variations required significantly lower weekly VKA maintenance doses than those with the wild‐type genotype (t‐test: P = 0·02). In contrast, in subjects without PPI use, the CYP2C9 genotype had no significant influence on oral VKA dose requirements. Further, the combined CYP2C9/VKORC1 genotype was a significant predictor for VKA dose requirements [linear regression: estimate: ?1·47, standard error: 0·58 (P = 0·01)]. In conclusion, in carriers of CYP2C9 gene variations, the interference with the VKA metabolism is modified by PPI co‐medication and the VCKORC1 genotype. Preceding knowledge of the genetic profile and the awareness for potentially occurring severe over‐anticoagulation problems under PPI co‐medication could contribute to a safer and personalized VKA pharmacotherapy.     

The optimal intensity of vitamin K antagonists in patients with mechanical heart valves: a meta-analysis

OBJECTIVES: The purpose of this study was to compare two different intensities of vitamin K antagonists (VKA) among patients with mechanical heart valves using meta-analytic techniques. BACKGROUND: Patients with mechanical heart valves are at increased risk for valve thrombosis and systemic embolism, which can be reduced by VKA. The range of optimal intensity of VKA is still a matter of debate. METHODS: A computerized search in the PubMed database was made for relevant articles. A meta-analysis was performed of all eligible studies with data on the incidences of thromboembolic and bleeding complications in patients with mechanical heart valve prostheses during different intensities of VKA therapy. The studies were classified into low-intensity VKA therapy (mean target international normalized ratio [INR] of 3.0 or lower) or high-intensity VKA therapy (mean target INR above 3.0). RESULTS: Thirty-five eligible studies were identified, including in total 23,145 patients, who were studied for 108,792 patient-years. For patients with an aortic valve, high intensity resulted in a lower incidence of thromboembolic events (risk ratio [RR] = 0.73, p < 0.0001); however, the incidence of bleeding was increased (RR = 1.23, p < 0.0001). In the mitral valve group, the incidence rate for thromboembolism was lower in the high-intensity group (RR = 0.74, p < 0.0001), without a significantly increased bleeding incidence (RR = 1.08, p = 0.0524). The total number of thromboembolic and bleeding events was decreased in the high-intensity group compared with low-intensity VKA therapy for both aortic and mitral valve prostheses (RR = 0.94 [p = 0.0067] and 0.84 [p < 0.0001]), respectively. CONCLUSIONS: This meta-analysis shows that both aortic and mitral valves will benefit from a treatment strategy with a target INR higher than 3.0.     

Therapeutic target values in oral anticoagulation — Justification of Dutch policy and a warning against the so-called moderate-intensity regimens

Summary Careful scrutiny of relevant thrombosis prevention studies in the light of recent knowledge on the responsiveness to the anticoagulant defect of the various prothrombin time assays used in these studies casts serious doubts on the adequacy of the so-called moderateintensity warfarin regimens, currently recommended by British and North American experts, in the majority of clinical situations. As long as there is strict laboratory monitoring, more intensive anticoagulation provides satisfactory prevention of thromboembolic events. The Federation of Dutch Thrombosis Centers recommends a target of 3.0 International Normalized Ratio (INR) for the primary and secondary prevention of venous thrombosis and thromboembolism, 3.5 INR in case of recurrence under the former regimen and for patients at risk for a cardiogenic embolism from any source (including tissue heart valve replacement) and those with atherothrombotic disease, and 4.0 INR for patients with a mechanical heart valve prosthesis. The risk of hemorrhage at such levels of anticoagulation remains acceptable.     

The JAK2 46/1 haplotype is a risk factor for myeloproliferative neoplasms in Chinese patients

The presence of JAK2 V617F is associated with an inherited JAK2 46/1 haplotype, a risk factor for myeloproliferative neoplasms (MPN) in Caucasian populations. Whether the JAK2 46/1 haplotype is also a risk factor in the Chinese population is unknown. We assessed for the JAK2 46/1 haplotype and JAK2 V617F mutation in 225 MPN patients and 226 controls using a tagged SNP rs12340895. The allele frequencies of the JAK2 46/1 haplotype were distinct among different subtypes of MPN patients. The allele frequency was significantly higher in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) than that in controls, with PV patients having the highest allele frequency (0.58, P?=?6.00E?15). The distribution of rs12340895 genotypes in the JAK2 V617F mutated MPN patients was significantly different from that in controls (P?=?1.67E?15). The percentage of GG genotype in controls was 2.2?%, but 31.0?% in JAK2 V617F-positive MPN patients. All the PV, ET, and PMF patients with the GG genotype also exhibited the V617F mutation. Compared to that of controls, the difference in genotype distribution in PV patients was the most significant (P?=?4.83E?21), followed by ET (P?=?2.07E?05) and PMF (P?=?1.99E?04). Our results suggest that the JAK2 46/1 haplotype is a risk factor for MPN in the Chinese population, and patients with GG genotype in rs12340895 locus are susceptible to JAK2 V617F mutation.     

Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin

This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 ?1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1 year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3 months. CYP2C9*3, VKORC1 ?1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95 % confidence interval (CI) 1.57–6.01] and minor hemorrhage (HR 3.28, 95 % CI 1.62–6.65), but not major hemorrhage (HR 0.44, 95 % CI 0.04–4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) ≥4 (HR 2.92, 95 % CI 1.08–7.85). VKORC1 ?1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan–Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (P = 0.001), but not for patients with VKORC1 ?1639 G/A or CYP4F2 rs2108622 genotype (P = 0.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation.     

Interaction of vitamin K antagonists with heparin affect monitoring by activated clotting times

Background

Unfractionated heparin is recommended during atrial fibrillation (AF) ablation to achieve activated clotting time (ACT) above 250–300 s to prevent clot. Many patients on therapeutic international normalised ratio (INR) undergo AF ablation procedures; however, it is unknown whether they require less heparin to achieve similar ACT levels.

Methods

During AF ablation, the ACT was measured before and 10 min after administration of i.v. unfractionated heparin in patients with and without anticoagulation. The association of INR, heparin, pre-procedure ACT and body weight with ACT after heparin administration was tested using multivariable linear regression models.

Results

The subjects of this study were 149 patients undergoing AF ablation, among them 40 (27%) with subtherapeutic INR?<?2, 79 (53%) with an INR between 2 and 3, and 30 (20%) patients with INR?>?3. Baseline ACT was associated with INR (r?=?0.33, p?<?0.001). After a mean of 8,685?±?2,015 U (range, 5,000–15,000 IU) unfractionated heparin, univariate predictors of ACT were baseline INR (p?<?0.001), heparin dose (p?=?0.012) and baseline ACT (p?=?0.027). In the multivariable model, baseline INR (part r?=?0.64, p?<?0.001) and heparin dose (part r?=?0.33, p?<?0.001) strongly predicted post-heparin ACT. Estimated from the regression model, the heparin dose reductions by approximately one third in those with an INR of 2–3 and by at least two thirds in those with an INR above 3 may be favourable. Over the following 3 months, no thromboembolism and acute bleeding were observed.

Conclusion

The INR was the strongest predictor of post-heparin ACT, even more important than the heparin dose itself. The reduction of heparin dose by one third if INR is between 2–3 and by two thirds if INR is above 3 may be favourable.     

Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates

Poor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the -1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ≥ 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs.     

Association of Rsa polymorphism of the estrogen receptor-β gene with rheumatoid arthritis

To investigate the possible influence of the single nucleotide polymorphism (SNP) of the estrogen receptor-β gene, rs1256049 (Rsa) in exon 5, on the frequency of rheumatoid arthritis (RA), 263 RA patients and 174 control subjects with osteoarthritis (OA) were recruited. Rsa polymorphism was detected using a PCR–RFLP, Polymerase Chain Reaction—Restriction Fragment Length Polymorphism method. The occurrence of both mutant allele (G) and genotype (GG) were significantly higher in RA than in OA patients (allele P?=?0.008, OR: 1.501, 95%CI: 1.12–2.02). In RA patients, GG genotype frequency was higher in severe RA patients than mild RA patients. Moreover, there was significant difference between severe RA patients and OA patients (P?=?0.009), also the allele distribution was significant different between severe RA, mild RA, and OA patients (P?=?0.025, 95%CI?=?0.61–0.93). With respect to gender, GG genotype was statistically more frequent in female RA patients than that of OA, while such an association was not observed in men. Above all, the presence of the GG genotype could be a risk factor for RA and such trend might be different in gender, although additional larger scale study is needed.     

Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis

OBJECTIVE: To examine the relationship between international normalized ratio (INR) and outcomes (major bleeding events and strokes) in patients with atrial fibrillation (AF) receiving anticoagulation with warfarin. METHODS: A systematic review and metaanalysis of studies published in the English language between January 1, 1985, and October 30, 2002, was performed. MEDLINE (PubMed), Current Contents, and relevant reference lists were searched. Studies enrolling patients with nonvalvular AF receiving warfarin anticoagulation were eligible for inclusion if they reported stroke and/or major bleeding events in relation to INR, or time spent in therapeutic range. The risk of bleeds in overanticoagulated patients (INR > 3) and the risk of strokes in underanticoagulated patients (INR < 2) were assessed. RESULTS: Twenty-one studies (6,248 patients) met all inclusion criteria. Of the 21 studies, a target conventional INR of 2 to 3 was used in 9 studies. An INR < 2, compared with an INR > or = 2, was associated with an odds ratio (OR) for ischemic events of 5.07 (95% confidence interval [CI], 2.92 to 8.80). An INR > 3, compared with an INR < or = 3, was associated with an OR for bleeding events of 3.21 (95% CI, 1.24 to 8.28). On average, in the four studies with a target INR range of 2 to 3, patients with AF receiving warfarin spent 61% of time within, 13% of time above, and 26% below the therapeutic range. CONCLUSION: Available evidence indicates that in patients with nonvalvular AF, the risk of ischemic stroke with insufficient warfarin anticoagulation (INR < 2), and the risk of bleeding events with overanticoagulation (INR > 3) are significantly higher relative to patients with AF maintained within the recommended INR of 2 to 3. However, the published data are sparse, heterogeneous, and primarily reported from clinical trials. More studies evaluating clinical outcomes in relation to INR are needed, especially in a real-world setting.     

Patient-Specific Tailored Intervention Improves INR Time in Therapeutic Range and INR Variability in Heart Failure Patients

Background

Many patients with heart failure need anticoagulants, including warfarin. Good control is particularly challenging in heart failure patients, with <60% of international normalized ratio (INR) measurements in the therapeutic range, thereby increasing the risk of complications. This study aimed to evaluate the effect of a patient-specific tailored intervention on anticoagulation control in patients with heart failure.

Therapie der Beinvenenthrombose

Current antithrombotic therapy of deep vein thrombosis (DVT) consists of an initial course of heparin, followed by the secondary prevention with oral anticoagulation (OAC). Low molecular weight heparin has several advantages over unfractionated heparin, however, renal insufficiency has to be observed to avoid accumulation. The synthetic pentasaccharide Fondaparinux is a factor Xa inhibitor, that will shortly be available for the initial treatment of DVT. Oral anticoagulation with vitamin K antagonists (VKA) is highly effective, the standard target INR is 2.0-3.0. For a first episode of DVT the duration of OAC usually is six months, but has to be adjusted according to the estimated risk for recurrence. Because of the narrow therapeutic window of VKA, low molecular weight heparins are increasingly being used for secondary prevention in patients with an increased risk for bleeding, mostly in 1/2-therapeutic dose. At present, several new antithrombotic agents are being studied and may become available shortly for DVT treatment.     

Rationale and design of VENTURE-AF: a randomized,open-label,active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial fibrillation

Purpose

To evaluate the safety of uninterrupted rivaroxaban, a novel oral anticoagulant that directly inhibits factor Xa, and a vitamin K antagonist (VKA) in eligible adult patients with nonvalvular AF (NVAF) who are scheduled for a catheter ablation.

Methods/design

This is a prospective, randomized, open-label, active-controlled, global multicenter safety study of up to 250 randomized patients. Eligible patients with paroxysmal or persistent NVAF, a left ventricular ejection fraction >40 %, and a creatinine clearance >50 mL/min will be randomized 1:1 to rivaroxaban 20 mg orally once daily or to dose-adjusted oral VKA (recommended international normalized ratio (INR) 2.0–3.0) and stabilized on anticoagulation therapy for 1–7 days (if no intracardiac thrombus on transesophageal echocardiogram (TEE) immediately prerandomization/post-randomization or if 3 weeks of sufficient anticoagulation is documented) or for 4–5 weeks (if no TEE, no documented 3 weeks of sufficient anticoagulation, or by patient choice). During catheter ablation, heparin will be administered (ACT-targeted range?=?300–400 s) after catheter ablation, and VKA will be managed per usual care. The next dose of rivaroxaban will be provided at least 6 h after establishment of hemostasis. The primary endpoint will be the incidence of post-procedure major bleeding events observed during the first 30?±?5 days post-ablation. Secondary endpoints will include post-procedure thromboembolic events, additional bleeding, time-to-event, and medication adherence.

Relevance

This study is intended to provide information about the safety characteristics of rivaroxaban in patients with NVAF undergoing catheter ablation.     

Worldwide Management of Oral Anticoagulant Therapy: the ISAM Study

A multicenter, observational, retrospective, cross-sectional study of patients, receiving oral anticoagulation therapy (OAT) for stroke prophylaxis in chronic non-valvular atrial fibrillation (NVAF) was conducted in the US, Canada, France, Italy and Spain according to their predominant model of care [routine medical care (RMC) or Anticoagulation Clinic care (ACC)]. The study objectives were to assess anticoagulation control (time in target range), and to describe the features of the local model of care. Consecutive patients were recruited on the basis of a minimum of 60 days of oral anticoagulant treatment over a 12 month period, and clinic and physician details were captured by means of a structured face-to-face or telephone interview. Time in therapeutic range (TTR) was calculated by using linear interpolation between INR values. A total of 1511 patients were recruited, of whom 1445 were included in the analysis of TTR. TTR was higher in ACC (69.5% and 64.9% for Italy and Spain, respectively) with respect to RMC (58.1%, 62.8% and 59.3% for the US, Canada and France, respectively). Mean intervals between INR determinations were between 3 and 4 weeks. Dose changes in case of INR outside therapeutic range were more frequent in Spain and less frequent in France. Striking differences were observed in type of VKA used, specialists involved in patient management, and dosage instructions. Studying of anticoagulation management based on local models of care highlights important discrepancies among countries and suggests further standardization of the management of this important therapy is necessary.     

SAMe-TT2R2 Score,Time in Therapeutic Range,and Outcomes in Anticoagulated Patients with Atrial Fibrillation

BackgroundOral anticoagulation is highly effective in preventing stroke and mortality in nonvalvular atrial fibrillation patients. However, the efficacy and safety of vitamin K antagonists (the main oral anticoagulation drug used) strongly depends upon the quantity of anticoagulation control, as reflected by the average percentage of the time in therapeutic range of international normalized ratio 2.0-3.0. An easy, simple prediction of which atrial fibrillation patients are likely to do well on vitamin K antagonists (with good average time in therapeutic range) could guide decision-making between using vitamin K antagonists (eg, warfarin) and non-vitamin K antagonist oral anticoagulants.Methods and ResultsIn a consecutive cohort of nonvalvular atrial fibrillation patients attending our anticoagulation clinic, we tested the hypothesis that the new Sex, Race, Medical history, Tobacco use, Race (SAMe-TT₂R₂) score was a predictor for good average time in therapeutic range, and second, this would translate into adverse events in a “real world” cohort of patients with nonvalvular atrial fibrillation. The incidence of bleeding, adverse cardiovascular events (including stroke/thromboembolism), and mortality during the follow-up was higher with increasing SAMe-TT₂R₂ score. The SAMe-TT₂R₂ score was predictive for the composite of all adverse events (hazard ratio 1.32 [95% Confidence Interval 1.17-1.50]; P <.001), adverse cardiovascular events (1.52 [1.28-1.83]; P <.001), and all-cause mortality (1.41 [1.16-1.67]; P = .001). A trend was also observed for major bleeding events (1.23 [0.99-1.53]; P = .059).ConclusionIn a “real world” cohort of consecutive patients with nonvalvular atrial fibrillation, a high SAMe-TT₂R₂ score (reflecting poor anticoagulation control with poor time in therapeutic range) was associated with more bleeding, adverse cardiovascular events, and mortality during follow-up.