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Journal of Thrombosis and Haemostasis :... May 2017Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients... (Comparative Study)
Comparative Study
Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP < 400. Conclusion In severe hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients.
Topics: Acenocoumarol; Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Case-Control Studies; Cross-Sectional Studies; Drug Monitoring; Female; Hemophilia A; Hemostasis; Humans; International Normalized Ratio; Kinetics; Male; Middle Aged; Phenprocoumon; Severity of Illness Index; Thrombin; Vitamin K; Young Adult
PubMed: 28296129
DOI: 10.1111/jth.13674 -
Journal of Thrombosis and Haemostasis :... Mar 2017Essentials Prospective studies of pharmacogenetic-guided (PG) coumarin dosing produced varying results. EU-PACT acenocoumarol and phenprocoumon trials compared PG and... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Essentials Prospective studies of pharmacogenetic-guided (PG) coumarin dosing produced varying results. EU-PACT acenocoumarol and phenprocoumon trials compared PG and non-PG dosing algorithms. Sub-analysis of EU-PACT identified differences between trial arms across VKORC1-CYP2C9 groups. Adjustment of the PG algorithm might lead to a higher benefit of genotyping.
SUMMARY
Background The multicenter, single-blind, randomized EU-PACT trial compared the safety and efficacy of genotype-guided and non-genetic dosing algorithms for acenocoumarol and phenprocoumon in patients with atrial fibrillation or deep vein thrombosis. The trial showed no differences in the primary outcome between the two dosing strategies. Objectives To explore possible reasons for the lack of differences between trial arms by performing a secondary analysis of EU-PACT data in order to evaluate the performance of both dosing algorithms across VKORC1-CYP2C9 genetic subgroups. Patients/Methods Anticoagulation control measured according to an International Normalized Ratio (INR) below (INR of < 2), within (INR of 2-3) and above (INR of > 3) the therapeutic range was compared across VKORC1-CYP2C9 subgroups. Owing to a low number of patients in each subgroup, trials for acenocoumarol and phenprocoumon were combined for analysis. Results Four weeks after therapy initiation, genotype-guided dosing increased the mean percentage of time in the therapeutic INR range (PTIR) in the VKORC1 GG-CYP2C9*1*1 subgroup as compared with the non-genetic dosing (difference of 14.68%, 95% confidence interval [CI] 5.38-23.98). For the VKORC1 AA-CYP2C9*1*1 subgroup, there was a higher risk of under-anticoagulation with the genotype-guided algorithm (difference of 19.9%; 95% CI 11.6-28.2). Twelve weeks after therapy initiation, no statistically significant differences in anticoagulation control between trial arms were noted across the VKORC1-CYP2C9 genetic subgroups. Conclusions EU-PACT genetic-guided dose initiation algorithms for acenocoumarol and phenprocoumon could have predicted the dose overcautiously in the VKORC1 AA-CYP2C9*1*1 subgroup. Adjustment of the genotype-guided algorithm could lead to a higher benefit of genotyping.
Topics: Acenocoumarol; Aged; Algorithms; Anticoagulants; Atrial Fibrillation; Cytochrome P-450 CYP2C9; Data Interpretation, Statistical; Female; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Pharmacogenetics; Phenprocoumon; Prospective Studies; Single-Blind Method; Treatment Outcome; Venous Thrombosis; Vitamin K; Vitamin K Epoxide Reductases
PubMed: 28063245
DOI: 10.1111/jth.13615 -
Journal of Thrombosis and Haemostasis :... Mar 2017Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for... (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
Essentials The EU-PACT trial was used to investigate age on the interaction between coumarins and genotype. The results support the use of genotype-guided dosing for phenprocoumon in patients < 75 years. For patients ≥ 75 years the phenprocoumon algorithm should be revised and further tested. No influence of comorbidities and co-current drug use was found that could explain the differences.
SUMMARY
Background Age seemed to affect the interaction between coumarins and genotype in the acenocoumarol and phenprocoumon arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial. Objectives To investigate the effect of genotype-guided dosing stratified by age and the potential factors causing a difference. Patients/Methods Data from the acenocoumarol/phenprocoumon arm of the EU-PACT trial were used. The percentages of time below the therapeutic range, time above the therapeutic range and time in the therapeutic range (TTR) during the initial 12 weeks of therapy were compared between the genotype-guided group and the control group among younger (< 75 years) and older (≥ 75 years) patients by the use of independent t-tests, and adjusted for sex, height, weight and co-medications by the use of linear regression. Results Among younger phenprocoumon users, TTR during the first 12 weeks in the genotype-guided group (n = 55) was 9.5% (95% confidence interval [CI] 1.3 to 17.8) higher than in the control group (n = 63), with a remarkably lower percentage of time above this range (difference: - 9.6%, 95% CI - 19.0 to - 0.2) and a similar time below this range. Older patients dosed by the genotype-guided algorithm (n = 24) spent more time above the range (difference: 27.5%, 95% CI 12.9 to 42.0). For acenocoumarol users, there were no significant differences between the genotype-guided and control groups for most outcomes, except for a lower percentage of time below the range among older patients. Conclusions The genotype-guided algorithm for phenprocoumon in the EU-PACT trial benefitted younger patients more, but for older patients the algorithm needs to be revised and tested in further research.
Topics: Acenocoumarol; Age Factors; Aged; Aged, 80 and over; Algorithms; Anticoagulants; Comorbidity; Cytochrome P-450 CYP2C9; Europe; Female; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Pharmacogenetics; Phenprocoumon; Time Factors; Treatment Outcome; Vitamin K Epoxide Reductases
PubMed: 27992949
DOI: 10.1111/jth.13601 -
PloS One 2016Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was...
BACKGROUND
Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was initiated to search for new biomarkers that predict bleeding in these patients.
OBJECTIVES
To describe the outline and objectives of BLEEDS and to examine whether the study population is generalizable to other VKA treated populations.
METHODS
A cohort was created consisting of all patients starting VKA treatment at three Dutch anticoagulation clinics between January-2012 and July-2014. We stored leftover plasma and DNA following analysis of the INR.
RESULTS
Of 16,706 eligible patients, 16,570 (99%) were included in BLEEDS and plasma was stored from 13,779 patients (83%). Patients had a mean age of 70 years (SD 14), 8713 were male (53%). The most common VKA indications were atrial fibrillation (10,876 patients, 66%) and venous thrombosis (3920 patients, 24%). 326 Major bleeds occurred during 17,613 years of follow-up (incidence rate 1.85/100 person years, 95%CI 1.66-2.06). The risk for major bleeding was highest in the initial three months of VKA treatment and increased when the international normalized ratio increased. These results and characteristics are in concordance with results from other VKA treated populations.
CONCLUSION
BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment.
Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Longitudinal Studies; Male; Middle Aged; Phenprocoumon; Prognosis; Risk Factors; Venous Thrombosis; Vitamin K
PubMed: 27935941
DOI: 10.1371/journal.pone.0164485 -
JACC. Cardiovascular Interventions Jan 2017The aims of this study were to assess the impact of atrial fibrillation (AF) on outcome in transfemoral aortic valve replacement (TAVR) and to evaluate the safety and... (Comparative Study)
Comparative Study
OBJECTIVES
The aims of this study were to assess the impact of atrial fibrillation (AF) on outcome in transfemoral aortic valve replacement (TAVR) and to evaluate the safety and efficacy of apixaban compared with a vitamin K antagonist (VKA) in patients with AF after TAVR.
BACKGROUND
Non-VKA oral anticoagulant agents have not been systematically used in patients with AF after TAVR.
METHODS
Of the 617 patients enrolled, 55.9% (n = 345) were in sinus rhythm and 44.1% (n = 272) in AF. Clinical follow-up was performed after 30 days and 12 months.
RESULTS
The early safety endpoint at 30 days was significantly more frequent in patients with AF compared with those in sinus rhythm (23.2% vs. 11.0%; p < 0.01). During 12-month follow-up, the secondary endpoint of all-cause mortality and stroke was significantly higher in patients with AF (20.6% vs. 9.7%; p = 0.02), driven by a significantly higher rate of all-cause mortality (19.1% vs. 7.8%; p = 0.01). Among patients with AF, 141 (51.8%) were treated with apixaban and 131 (48.2%) with a VKA. There was a significantly lower rate of the early safety endpoint in patients with AF treated with apixaban compared with patients treated with a VKA (13.5% vs. 30.5%; p < 0.01), with a numerically lower stroke rate (2.1% vs. 5.3%; p = 0.17) at 30 days and 12 months (1.2% vs. 2.0%; p = 0.73) of follow-up.
CONCLUSIONS
In patients undergoing TAVR, AF was associated with a significantly higher rate of all-cause mortality throughout 12 months follow-up. The early safety endpoint in patients with AF on apixaban was significantly less frequent compared with patients receiving a VKA.
Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Disease-Free Survival; Factor Xa Inhibitors; Female; Femoral Artery; Humans; Kaplan-Meier Estimate; Male; Phenprocoumon; Proportional Hazards Models; Prospective Studies; Punctures; Pyrazoles; Pyridones; Registries; Risk Factors; Stroke; Time Factors; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K
PubMed: 27916486
DOI: 10.1016/j.jcin.2016.10.023 -
Medicine Nov 2016Oral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional)...
RATIONALE
Oral anticoagulants and painkillers, some with an additional effect on the coagulation system, are widely used and are therefore prone to abuse and (intentional) overdose. We report the case of a patient with a massive mixed anticoagulant intoxication.
PATIENT CONCERNS
The patient had ingested 1960 mg rivaroxaban, 31.5 mg phenprocoumon, 1425 mg diclofenac, and 21,000 mg metamizole in suicidal intention.
DIAGNOSES
Massive mixed anticoagulant overdose.
INTERVENTIONS
The patient was closely monitored. The phenprocoumon overdose was treated by the administration of vitamin K and PCC.
OUTCOMES
Despite the massive inhibition of the coagulation system, the patient did not experience bleeding apart from a slight gross hematuria.
LESSONS
Despite the ingestion of a massive amount of rivaroxaban, the plasma levels were not as high as feared, due to the ceiling effect of rivaroxaban absorption. Elimination occurred according to the half-life of rivaroxaban and was not unduly prolonged by the ingested quantity.
Topics: Anticoagulants; Cyclooxygenase Inhibitors; Diclofenac; Factor Xa Inhibitors; Humans; Male; Phenprocoumon; Rivaroxaban; Young Adult
PubMed: 27858919
DOI: 10.1097/MD.0000000000005343 -
European Journal of Clinical... Dec 2016The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). (Clinical Trial)
Clinical Trial
PURPOSE
The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs).
METHODS
We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test.
RESULTS
Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower.
CONCLUSIONS
Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.
Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Vitamin K
PubMed: 27709253
DOI: 10.1007/s00228-016-2138-6 -
Journal of Thrombosis and Haemostasis :... May 2016Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor...
UNLABELLED
Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case-crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores.
SUMMARY
Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events.
Topics: Acenocoumarol; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cohort Studies; Female; Fibrinolytic Agents; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Odds Ratio; Phenprocoumon; Proportional Hazards Models; Risk Factors; Vitamin K
PubMed: 26988994
DOI: 10.1111/jth.13306 -
Journal of Thrombosis and Haemostasis :... May 2016The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct... (Review)
Review
The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient-related and procedure-related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non-valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging.
Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Aortic Valve; Atrial Fibrillation; Elective Surgical Procedures; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Perioperative Care; Phenprocoumon; Prothrombin; Randomized Controlled Trials as Topic; Societies, Medical; Thromboembolism; Thrombosis; United States; Vitamin K; Warfarin
PubMed: 26988871
DOI: 10.1111/jth.13305 -
Cardiovascular Therapeutics Jun 2016Data evaluating the complications of pulmonary vein isolation (PVI) using second-generation cryoballoons (CB) related to different anticoagulation regimes are limited.... (Comparative Study)
Comparative Study Observational Study
The Total Incidence of Complications and the Impact of an Anticoagulation Regime on Adverse Events After Cryoballoon Ablation of Atrial Fibrillation: A Single-Center Study of 409 Patients.
AIM
Data evaluating the complications of pulmonary vein isolation (PVI) using second-generation cryoballoons (CB) related to different anticoagulation regimes are limited. This study evaluates the total complications and the impact of novel oral anticoagulants (NOACs) compared to phenprocoumon on adverse events in the setting of PVI using CB.
METHODS AND RESULTS
PVI was performed using second-generation CB by two experienced investigators. A total of 409 patients (58.9% male; mean age = 61 ± 10 years) with atrial fibrillation were included in this study. In group I, 150/409 (36.7%) patients received phenprocoumon therapy, and in group II, 259/409 (63.3%) patients were treated with NOACs (rivaroxaban: n = 193; dabigatran: n = 48; and apixaban: n = 18). In both groups, the rates of major complications were similar (group I [phenprocoumon]: four pts (2.7%) vs. Group II [NOACs]: seven pts (2.7%); P = 0.999). In this cohort, 275 patients were ablated with the bonus freeze protocol, and 134 patients were ablated without bonus freezes. The procedure duration significantly decreased with the bonus freeze protocol from 102.3 ± 24.6 min to 68.5 ± 16.2 min (P < 0.001). The impact of the bonus freeze on the postprocedural increase of C-reactive protein (CRP) levels was significant compared to the postprocedural CRP levels after procedures without the bonus freeze protocol (postprocedural CRP level+ bonus protocol: 1.6 ± 1.2 mg/L vs. postprocedural CRP level+ nonbonus protocol: 1.3 ± 1.3 mg/L; P = 0.04).
CONCLUSION
The incidence of adverse events in PVI using the second-generation CB with the periprocedural administration of NAOCs was not significantly different compared to phenprocoumon. Further, large-scale randomized studies are needed to evaluate the safety of two anticoagulation regimes comparing vitamin K antagonists and NOACs, as well as different NOAC regimes, in patients undergoing PVI using cryoballoon ablation.
Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Biomarkers; Cryosurgery; Dabigatran; Female; Germany; Humans; Incidence; Inflammation Mediators; Male; Middle Aged; Phenprocoumon; Postoperative Complications; Pulmonary Veins; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome
PubMed: 26880220
DOI: 10.1111/1755-5922.12178