Risk of traumatic intracranial haemorrhage is increased in older people exposed to oral anticoagulation with phenprocoumon.

BACKGROUND: Hospital admissions resulting from traumatic intracranial haemorrhages (TIH) in older people are increasing. There are concerns regarding an increased risk of a TIH in people taking oral anticoagulants (OAC) like phenprocoumon. AIMS: The aim of this study was to estimate the incremental risk of a TIH associated with OAC in older people. Furthermore, this study explored differences in risk according to functional status. METHODS: The study took data from a large German health insurance provider and combined hospital diagnoses with data regarding drug dispensing to estimate rates of a TIH in people with and without exposure to phenprocoumon. Analyses were stratified by sex and by severe functional impairment as disclosed by the long-term care insurance provider. RESULTS: Overall, exposure to OAC resulted in 2.7 times higher rates of TIH. People with severe functional impairment had a higher baseline risk of TIH than people without severe functional impairment. However, the incremental risk in those exposed to OAC was similar among people with and without severe functional impairment (standardised incidence rate difference 15.73 (95% CI 7.84; 23.61) and 12.10 (95% CI 9.63; 14.57) per 10,000 person-years, respectively). CONCLUSIONS: OAC increases the risk of TIH considerably. The incremental risk of TIH in those exposed to OAC is comparable between people with and without severe functional impairment. The presence of severe functional impairment per se should not exclude such patients from the potential benefits of OAC. For now, the prescription should be personalized based on individual fall risk factors and risk-taking behaviour.

Multistate methodology improves risk assessment under time-varying drug intake-a new view on pregnancy outcomes following coumarin exposure.

PURPOSE: Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques. METHODS: We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion. RESULTS: We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians. CONCLUSIONS: An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.

Use of vitamin K antagonists and risk of prostate cancer: Meta-analysis and nationwide case-control study.

Use of vitamin K antagonists (VKAs) has been suggested to reduce the risk of prostate cancer. We conducted a nested case-control study using Danish demographic and health data registries and summarized existing evidence in a meta-analysis. The case-control study included all Danish men aged 40-85 years with incident histologically verified prostate adenocarcinoma between 2005 and 2015 (cases). For each case, we selected 10 age-matched controls. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CI) for prostate cancer associated with long-term VKA use adjusted for concomitant drug use, medical history and socioeconomic status. Among 38,832 prostate cancer cases, 1,089 (2.8%) had used VKAs for 3 or more years compared to 10,803 (2.8%) controls yielding a crude OR of 1.01 (95% CI, 0.95-1.08). Multivariable adjustment for covariates had limited influence on the association (OR, 1.03; 95% CI, 0.97-1.10). We observed no dose-response relationship (e.g. OR for 5-10 years of use, 1.06 95% CI, 0.97-1.16). We included 8 studies in the meta-analysis reporting effect estimates from 0.51 (95% CI, 0.23-1.13) to 1.10 (95% CI, 0.94-1.40). Using random effect methods, a pooled effect estimate of 0.86 (95% CI, 0.70-1.05) was obtained; however, there was considerable across-study heterogeneity (I2 : 93.9%). In conclusion, we did not observe a reduced risk of prostate cancer associated with VKA use in this nationwide study and, taken together with previous study findings, a major protective effect of VKAs against prostate cancer seems unlikely.

Characteristics, treatment and outcome of bleeding after tooth extraction in patients on DOAC and phenprocoumon compared to non-anticoagulated patients-a retrospective study of emergency department consultations.

OBJECTIVES: Bleeding after tooth extraction range from minor bleeding to life-threating haemorrhagic shock and are among the leading complications in patients under oral anticoagulation with direct oral anticoagulants (DOACs) or phenprocoumon. Little is known about how anticoagulation in patients under DOAC or phenprocoumon alters the characteristics, treatment or outcome of bleeding events, in comparison to non-anticoagulated patients. METHODS: Patients admitted to a tertiary ED in Bern, Switzerland, from June 1st 2012 to 31st May 2016 with bleeding related to tooth extraction under DOAC, phenprocoumon or without anticoagulation, were compared. RESULTS: Out of 161,458 emergency consultations, 64 patients with bleeding from tooth extraction were included in our study. In anticoagulation groups, we found significantly more delayed bleeding events than in patients without anticoagulation (9 (81.3%) DOAC, 19 (86.4%) phenprocoumon, 8 (30.8%) no anticoagulation, p < 0.001). Anticoagulated patients had to stay longer in the ED than non-anticoagulated patients, with no significant difference between DOAC or phenprocoumon (hours: 4.8 (3.2-7.6 IQR) DOAC, 3.0 (2.0-5.5 IQR) phenprocoumon, p = 0.133; 2.7 (1.6-4.6) no anticoagulation; p = 0.039). More patients with anticoagulation therapy needed surgery than patients without anticoagulant therapy (11 (68.8%) DOAC, 12 (54.6%) VKA, p = 0.506; 7(26.9%) no anticoagulation; p = 0.020). CONCLUSIONS: Delayed bleeding occur more often in anticoagulated patients with both DOAC and phenprocoumon compared to patients without anticoagulation. Bleeding events in anticoagulated patients with DOAC and phenprocoumon equally need longer ED treatment and more frequent surgical intervention. CLINICAL RELEVANCE: Caution with delayed bleeding in anticoagulated patients with DOACs and phenprocoumon is necessary and treatment of bleeding is resource-demanding.

Effects of age and genetic variations in VKORC1, CYP2C9 and CYP3A4 on the phenprocoumon dose in pediatric patients.

AIM: To study the effects of clinical and genetic factors on the phenprocoumon dose requirement in pediatric patients and to develop a dosing algorithm. METHODS: Pediatric patients who used phenprocoumon were invited to participate in a retrospective follow-up study. Clinical information and genotypes of genetic variations in CYP2C9, VKORC1, CYP4F2, CYP2C18 and CYP3A4 were collected and tested with linear regression for association with phenprocoumon dose requirement. RESULTS: Of the 41 patients included in the analysis, age, VKORC1, CYP2C9*2/*3 and CYP3A4*1B were statistically significantly associated with dose requirement, and together explained 80.4% of the variability in phenprocoumon dose requirement. CONCLUSION: Our study reveals that age and genetic variations explain a significant part of the variability in phenprocoumon dose requirement in pediatric patients.

Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.

INTRODUCTION: Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. METHODS AND ANALYSIS: A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02933697,Pre-results.

Meta-Analysis of Genotype-Guided Versus Standard Dosing of Vitamin K Antagonists.

Vitamin K antagonist (VKA) is a commonly prescribed anticoagulant with a narrow therapeutic window. Genetic polymorphisms account for high VKA dosage variability. Hence, we performed an updated meta-analysis of all randomized clinical trials (RCTs) comparing genotype-guided VKA versus standard dosing algorithms. We conducted a systematic search of electronic databases from inception to October 2017 for all RCTs. The primary outcome was the percentage of time in therapeutic range (TTR). Secondary outcomes were international normalized ratio >4, major and all bleeding events, thromboembolism, adverse and serious adverse events, and all-cause mortality. We calculated the weighted mean difference for the primary outcome and risk ratio (RR) for secondary outcomes using a random-effect model. We included 20 RCTs and analyzed a total of 5,980 adult patients. Our pooled analysis showed greater improvement in TTR for the genotype-guided group in comparison with the standard group (mean difference 3.41%, 95% confidence interval [CI] 0.71 to 6.10, p = 0.01). In addition, there were significant reductions in major and all bleeding events ((RR 0.35, 95% CI 0.20 to 0.63, p = 0.0004) and (RR 0.79, 95% CI 0.66 to 0.95, p = 0.01), respectively). However, there were no significant differences between the groups for international normalized ratio >4 (RR 0.89, 95% CI 0.80 to 1.00, p = 0.06), thromboembolism (RR 0.81, 95% CI 0.56 to 1.17, p = 0.25), serious adverse events (RR 0.79, 95% CI 0.61 to 1.03, p = 0.08), any adverse events (RR 0.94, 95% CI 0.88 to 1.01, p = 0.07), or all-cause mortality (RR 0.73, 95% CI 0.32 to 1.66, p = 0.46). In conclusion, genotype-guided VKA dosing can improve the TTR and reduce the risk for bleeding episodes, in comparison with standard dosing algorithms.

Effectiveness and Safety of Non-Vitamin K Oral Anticoagulants in Comparison to Phenprocoumon: Data from 61,000 Patients with Atrial Fibrillation.

All pivotal trials have evaluated non-vitamin K oral antagonists (NOACs) against warfarin. However, in some regions of the world, phenprocoumon is the most widely used vitamin K antagonist (VKA). There is little evidence documenting effectiveness and safety of NOACs compared with phenprocoumon in atrial fibrillation (AF). A retrospective cohort study using a German claims database was conducted to assess effectiveness (stroke, systemic embolism [SE]) and safety (bleeding leading to hospitalization) during therapy with NOACs and phenprocoumon in 61,205 AF patients. Hazard ratios (HRs) for effectiveness and safety outcomes were derived from Cox proportional hazard models, adjusting for baseline characteristics. Propensity score matching was performed as a sensitivity analysis. As a prespecified subgroup analysis, the effects of reduced NOAC dosing were compared with phenprocoumon. A total of 61,205 patients were identified in whom phenprocoumon (n = 23,823, 38.9%), apixaban (n = 10,117, 16.5%), dabigatran (n = 5,122, 8.4%), or rivaroxaban (n = 22,143, 36.2%) was initiated. After adjusting for baseline confounders, all three NOACs tested had significantly lower risks of stroke/SE compared with phenprocoumon (apixaban-HR: 0.77, 95% CI: 0.66-0.90; dabigatran-HR: 0.74, 95% CI: 0.60-0.91; rivaroxaban-HR: 0.86, 95% CI: 0.76-0.97). Apixaban (HR: 0.58, 95% CI: 0.49-0.69) and dabigatran (HR: 0.64, 95% CI: 0.50-0.80) were associated with lower bleeding risks than phenprocoumon, whereas the risk was similar for rivaroxaban and phenprocoumon. All three NOACs showed reduced risk of intracranial bleeding compared with phenprocoumon. Reduced doses of NOACs were predominantly used in patients with advanced age and comorbidities with generally similar effectiveness and safety benefits compared with phenprocumon as standard-dose NOACs.

Safety of Uninterrupted Periprocedural Edoxaban Versus Phenprocoumon for Patients Who Underwent Left Atrial Catheter Ablation Procedures.

Data about the safety of edoxaban in patients who underwent left atrial (LA) radiofrequency (RF) ablation procedures are lacking. This study sought to compare the safety of uninterrupted edoxaban with uninterrupted phenprocoumon administration during LA RF ablation for atrial fibrillation and atrial tachycardia. In total, 231 patients (mean age 64 ± 11years, male 71%) who underwent LA RF ablation under continuous oral anticoagulation (OAC) with edoxaban or phenprocoumon were included in the study. Patients on uninterrupted edoxaban (60 mg or 30 mg/day for at least 4 weeks) were matched for gender, age and type of arrhythmia with 2 patients on uninterrupted phenprocoumon (international normalized ratio 2 to 3). We identified 77 consecutive patients on edoxaban and n = 154 patients on phenprocoumon. Heparin was administered periprocedurally to achieve an activated clotting time of 280 to 300 seconds. No protamine was administered periprocedurally. The primary end point was a composite of bleeding, thromboembolic events, and death. The primary end point was met in 9 patients in the edoxaban group and in 22 patients in the phenprocoumon group (p = 0.69). No patient in either group died or had a thromboembolic complication. No major bleeding complication was observed in the edoxaban group, whereas one was found in 1 patient in the phenprocoumon group (p ≥0.99). Minor bleeding complications occurred in 9 patients (12%) in the edoxaban group and in 21 patients (14%) in the phenprocoumon group (p = 0.84). Uninterrupted OAC with edoxaban appeared to be as safe as uninterrupted OAC with phenprocoumon in patients who underwent LA RF ablation procedures.

Non-vitamin K-dependent oral anticoagulants have a positive impact on ischaemic stroke severity in patients with atrial fibrillation.

Aims: Several studies showed reduced stroke severity in patients with atrial fibrillation (AF) if the international normalized ratio (INR) was ≥ 2 at stroke onset. There are no respective data for non-vitamin K-dependent oral anticoagulants (NOACs). The aim of this study was to compare the impact of NOAC or phenprocoumon intake on stroke severity. Methods and results: In this single-centre observational study, 3669 patients with acute ischaemic stroke were retrospectively analysed regarding AF status and medication immediately before admission. Using multivariable regression, we analysed the association of pre-admission anticoagulation with severe stroke (National Institutes of Health Stroke Scale score ≥ 11) on admission and poor outcome at discharge (modified Rankin scale score > 2). Before the index stroke, 655 patients had known AF and a CHA2DS2-VASc score ≥ 2. While 325 (49.6%) patients were anticoagulated, 159 (24.3%) were prescribed a NOAC and 75 (11.5%) phenprocoumon patients had an INR ≥ 2 on admission. Compared with AF patients without medical stroke prevention, an INR ≥ 2 [OR 0.23 (95% CI 0.10-0.53)] or NOAC intake [OR 0.48 (95% CI 0.27-0.86)] were associated with a lower probability of severe stroke after adjustment for confounders, while an INR < 2 [OR 0.62 (95% CI 0.33-1.16)] was not. Adjusted odds ratios for poor functional outcome at hospital discharge were 0.47 (95% CI 0.27-0.84) for NOAC patients, 0.33 (95% CI 0.17-0.65) for INR ≥ 2 and 0.61 (95% CI 0.32-1.16) for INR < 2. Conclusion: NOAC intake before stroke did reduce the probability of severe stroke on hospital admission and poor functional outcome at hospital discharge as similarly demonstrated for phenprocoumon patients with an INR ≥ 2 on admission.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

Use of oral anticoagulants in German nursing home residents: drug use patterns and predictors for treatment choice.

AIMS: Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA. METHODS: Using claims data (2010-2014), we studied a cohort of new nursing home residents aged ≥65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years. RESULTS: Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49-2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59-0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00-3.24), bleeding events and a recent hospitalization. During 2010-2014, the proportion of AF patients with a CHADS2 score ≥2 receiving OAC increased from 27% to 46%. CONCLUSIONS: NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring.

Idiopathic catastrophic thrombosis with happy ending.

A 59-year-old male patient suffered three life-threatening instent thromboses after an initial resuscitation due to an ST-segment elevation myocardial infarction of the anterior cardiac wall. With a high-risk profile for heparin-induced thrombocytopenia (HIT), he was placed on argatroban after the second reinfarction. Under this apparently appropriate treatment, a third reinfarction occurred, and the patient had to undergo high-risk cardiac bypass surgery. Later on, a deep vein thrombosis and an intracardiac thrombus formed. Despite a positive screening test for HIT and a single positive result in the heparin-induced platelet aggregation test, we are not convinced that HIT was the only underlying cause for this 'catastrophic thrombotic syndrome'. We speculate that a massive generation of thrombin, reflected in consistently high D dimers and the need of copious amounts of a direct thrombin inhibitor, triggered the set of events. With this case report, we want to raise awareness for cardiac complications in patients with complex clotting disorders and share our experience in the diagnostic and therapeutic management of such an unusual scenario.

Apixaban, rivaroxaban, and dabigatran use in patients undergoing catheter ablation for atrial fibrillation using the second-generation cryoballoon.

BACKGROUND: Data are limited on the safety of periprocedural anticoagulation with novel oral anticoagulants (NOACs) in patients undergoing pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB) for the treatment of atrial fibrillation. HYPOTHESIS: We hypothesized that the incidence of acute periprocedural complications in patients undergoing PVI do not differ between patients treated with VKA compared to NOACs. METHODS: In 200 consecutive patients (mean age, 64.3 _ 10.6 years; female, n = 83) with symptomatic atrial fibrillation, PVI using the second-generation 28-mm CB was performed. In patients treated with NOACs, the medication was stopped the day of the procedure and continued the evening after the procedure with a reduced dosage. Patients treated with phenprocoumon were continued on uninterrupted phenprocoumon with a target INR of 2 to 3. If INR was <2, bridging with low-molecular-weight heparin was performed. RESULTS: Forty-seven of 200 patients (23.5%) were treated with a vitamin K antagonist (VKA) and 55 (27.5%) were treated with apixaban, 67 (33.5%) with rivaroxaban, and 31 (15.5%) with dabigatran. Seven (3.5%) major complications occurred in the overall population. Major bleeding complications did not differ significantly between the 2 groups (P = 0.23). One patient taking VKA had a pericardial tamponade at the end of the procedure; 2 patients treated with apixaban developed a groin hematoma requiring surgical intervention. Transient ischemic attack occurred in 1 patient of the apixaban and rivaroxaban group. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran, compared with uninterrupted VKA, did not show a higher risk for major bleeding or ischemic complications in patients undergoing PVI using the second-generation CB.

How safe are NOACs compared with phenprocoumon after pulmonary vein isolation with the cryoballoon technique using purse-string suture closure?

INTRODUCTION: The aim of this observational study was to compare the postprocedural incidence of bleeding and thromboembolic complications associated with novel oral anticoagulants (NOACs) with that of interrupted and continuous phenprocoumon after pulmonary vein isolation (PVI) using a purse-string suture (PSS) closure of the puncture site. METHODS AND RESULTS: Consecutive patients who had undergone PVI via cryoballoon ablation were divided into the following groups: (1) interrupted phenprocoumon with heparin bridging (n=101), (2) continuous phenprocoumon targeting an internationally normalized ratio>2 (n=70), and (3) NOACs without bridging that were restarted 2-4h after the procedure (n=185). Protamine was not administered after venous closure with PSS at the end of the procedure. The total complication rate was significantly lower in group 3 than in groups 1 and 2 (1.62% vs. 6.93% vs. 7.14%, p=0.04). The hospital costs were lower and the hospital stay length was significantly shorter (4484±3742 vs. 6082±4044 Euro vs. 4908±2925, p=0.03; 1.94±1.67 vs. 2.70±1.80 vs. 2.19±1.30days, p<0.01). No thromboembolic event occurred. Vascular complications were the most common complications noted (80%). The occurrence of any complication led to a significantly longer hospital stay (5 vs. 2days, p<0.01) and higher costs (10,052±6241 Euro vs. 4747±3447, p<0.01). The vascular complication rate after PSS was independent of intraprocedural heparin dosage and activated clotting time. CONCLUSIONS: NOACs have a lower complication rate and appear to be safer in this setting than phenprocoumon. The hospital costs and hospital stay length after PVI was significantly reduced in patients treated with NOACs compared with phenprocoumon.

Increased Thromboembolic Events With Dabigatran Compared With Vitamin K Antagonism in Left Ventricular Assist Device Patients: A Randomized Controlled Pilot Trial.

BACKGROUND: Left ventricular assist device-supported patients are usually anticoagulated with a combination of aspirin and vitamin K antagonists. Long-term vitamin K antagonist therapy can be complicated by unstable international normalized ratio values and patient-related compliance problems. Therefore, direct thrombin inhibitors may represent an alternative to vitamin K antagonists. METHODS AND RESULTS: Thirty HeartWare ventricular assist device patients with stable renal function were planned for this prospective, randomized, open-label, single-center study. Patients were randomized to receive either phenprocoumon or dabigatran in addition to aspirin for long-term anticoagulation. Treatment duration was scheduled for 1 year and stopped after observation of a primary end point. Dabigatran dose was 110 and 75 mg BID in patients with normal or impaired renal function (glomerular filtration rate >80 mL/min or between 80 and 30 mL/min, respectively). The study was stopped prematurely for safety reasons after 16 patients (61±8 years, 1 female) were randomized. Thromboembolic events occurred in 4 subjects receiving dabigatran (50%) and in 1 receiving phenprocoumon (13%; P=0.28). No major bleeding was recorded, and no patient died during the study. Median time to treatment termination was significantly shorter in dabigatran patients (8.5 versus 12.0 months; P=0.015). CONCLUSIONS: Thromboembolic events on dabigatran led to early termination of a randomized controlled trial of dabigatran versus phenprocoumon in left ventricular assist device patients. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02872649.

Comparative risk of major bleeding with new oral anticoagulants (NOACs) and phenprocoumon in patients with atrial fibrillation: a post-marketing surveillance study.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective and safe as vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). All pivotal trials have compared NOACs to warfarin. However, other VKAs are commonly used, for instance phenprocoumon. PATIENTS AND METHODS: A retrospective cohort study using a German claims database assessed the comparative risks of bleeding leading to hospitalization during therapy with NOACs and phenprocoumon in AF patients. Endpoints consisted of major bleeding, gastrointestinal bleeding, and any bleeding. Data were collected from January 1, 2013 to March 31, 2015. Patients newly initiated on dabigatran, apixaban, rivaroxaban, or phenprocoumon were included. Hazard Ratios for bleeding events were derived from Cox proportional hazard models, adjusting for differences in baseline characteristics. Propensity score matching was performed as a sensitivity analysis. RESULTS: A total of 35,013 patients were identified, including 3138 on dabigatran, 3633 on apixaban, 12,063 on rivaroxaban, and 16,179 on phenprocoumon. Patients prescribed apixaban or phenprocoumon were older compared to those on dabigatran or rivaroxaban and had a higher CHA2DS2-VASc score. After adjusting for baseline confounders, apixaban was associated with lower risks of major bleeding (HR 0.68, 95% CI 0.51-0.90, p = 0.008), gastrointestinal bleeding (HR 0.53, 95% CI 0.39-0.72, p < 0.001), and any bleeding (HR 0.80, 95% CI 0.70-0.92, p = 0.002) compared to phenprocoumon. There were no significant differences in bleeding risk between dabigatran and phenprocoumon. Rivaroxaban was associated with more gastrointestinal bleeding (HR 1.39, 95% CI 1.21-1.60, p < 0.001) and any bleeding (HR 1.19, 95% CI 1.10-1.28, p < 0.001). Sensitivity analysis using propensity score matching confirmed these observations. CONCLUSIONS: Apixaban therapy is associated with a significantly reduced risk of bleeding compared to phenprocoumon. Bleeding risk with dabigatran was similar to that of phenprocoumon but bleeding risk with rivaroxaban was higher.

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

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.

Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment.

The aim of this observational cohort study was to specify the risk of the vitamin K antagonist (VKA) phenprocoumon during first trimester of pregnancy, in particular to estimate the risk of birth defects and spontaneous fetal loss. Four hundred eight pregnancies with phenprocoumon exposure were compared to 1,642 pregnancies neither exposed to VKA nor to other major teratogens or fetotoxicants. There was no typical warfarin embryopathy in our exposed cohort. However, the overall rate of major birth defects was significantly increased (7.4 % vs 2.3 %; adjusted odds ratio [ORadj] 2.14; 95 % confidence interval [CI] 1.4-3.4). With early cessation until five completed gestational weeks the birth defect risk was similar to the comparison cohort (2.4 % vs 2.3 %; ORadj 1.07; 95 % CI 0.2-3.6). With treatment duration exceeding seven gestational weeks the rate of major birth defects increased up to five-fold (10.8 % vs 2.3 %; ORadj 5.18; 95 % CI 2.0-11.6). The overall risk of spontaneous abortion (SAB) was 38.0 % vs 17.5 % in the comparison cohort (adjusted hazard ratio [HRadj] 2.9; 95 % CI 2.2-3.9). The treatment duration had a significant effect on the hazard of SAB (HRadj 1.12; 95 % CI 1.01-1.25 per each additional exposure week). Phenprocoumon and other VKA carry an embryotoxic risk. This risk seems to be time-dependent with a steep risk increase for birth defects and also for fetal loss after week 5. If maternal disease permits, VKA therapy should be switched to safer alternatives such as heparins immediately after early recognition of pregnancy.