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.

Microfluidic coagulation assay for monitoring anticoagulant therapy in acute stroke patients.

Reliable detection of anticoagulation status in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) is challenging but of importance especially in the emergency setting. This study evaluated the potential of a whole-blood clotting time assay based on Surface Acoustic Waves (SAW-CT) in stroke-patients. The SAW-technology was used for quick and homogenous recalcification of whole blood inducing a surface-activated clotting reaction quantified and visualised by real-time fluorescence microscopy with automatic imaging processing. In 20 stroke or transient ischaemic attack (TIA)-patients taking NOACs kinetics of SAW-CT were assessed and correlated to other coagulation parameters (PT, aPTT) and NOAC-plasma concentration measured by tandem mass spectrometry (LC-MS/MS). In 225 emergency patients with suspicion of acute stroke or TIA, SAW-CT values were assessed. Mean (± SD) SAW-CT in non-anticoagulated stroke patients (n=180) was 124 s (± 21). In patients on dabigatran or rivaroxaban, SAW-CT values were significantly higher 2 and 8 hours (h) after intake rising up to 267 seconds (s) (dabigatran, 2 h after intake) and 250 s (rivaroxaban, 8 h after intake). In patients on apixaban, SAW-CT values were only moderately increased 2 h after intake (SAW-CT 153 s). In emergency patients, SAW-CT values were significantly higher in NOAC and vitamin K antagonist (VKA)-treated as compared to non-anticoagulated patients. In conclusion, the SAW-CT assay is capable to monitor anticoagulant level and effect in patients receiving dabigatran, rivaroxaban and the VKA phenprocoumon. It has a limited sensitivity for apixaban-detection. If specific SAW-CT results were used as cut-offs, SAW-CT yields high diagnostic accuracy to exclude relevant rivaroxaban and dabigatran concentrations in stroke-patients.

Apixaban, Rivaroxaban, and Dabigatran in Patients Undergoing Atrial Fibrillation Ablation.

INTRODUCTION: Data on the novel oral anticoagulants (NOACS) during catheter ablation (CA) of atrial fibrillation (AF) are still limited. This study evaluated the periprocedural major complications (MC) of CA of AF, and compared Apixaban, Dabigatran, and Rivaroxaban with continuous phenoprocoumon. METHODS AND RESULTS: A total of 444 patients (mean age = 65.1 ± 9.4 years; 283 [64%] male) with paroxysmal (n = 180 [41%]), persistent (n = 256 [58%]), or longstanding-persistent AF were enrolled. CA was performed in all patients using radiofrequency energy in conjunction with a 3D-mapping system. MCs were defined according to the current guidelines. Continuous phenprocoumon-therapy was administered in 120/444 (27%) patients (group 1) and 324/444 (73%) patients were treated with NOACs (group 2; Dabigatran: n = 51 [15.7%]; Rivaroxaban: n = 193 [59.6%]; Apixaban: n = 80 [24.7%]). Procedure times were comparable between groups 1 and 2 (128.2 ± 39.7 minutes vs. 129.7 ± 51.2 minutes; P = 0.77). CHA2 DS2-Vasc (3.0 [2.0, 4.0)] vs. 2.0 [1.0, 3.0]; P < 0.01) and HASBLED scores (2.0 [2.0, 2.5] vs. 2.0 [1.0, 2.0]; P = 0.002) were higher in group 1 patients. The incidence of MCs in the overall group was 8/444 (2%) and was equally distributed between groups 1 and 2 (2/120 [2%] vs. 6/324 [2%], P = 0.90). The incidence of MCs was comparable between the three different NOACs. There were no significant differences between patients with and without MCs with regard to age, CHA2 DS2-Vasc-score or HASBLED-score. CONCLUSIONS: The major complication rate between all three NOACs currently available and continuous phenprocoumon during AF ablation seem to be comparable. Complication rates were similar between patients treated with the three different available NOACs.

Possible drug-drug interaction between high-dose esomeprazole and phenprocoumon.

PURPOSE: It is established that omeprazole increases (R)+ warfarin levels with around 10 %. Whether (es)omeprazole also increase the plasma levels of acenocoumarol or phenprocoumon is still uncertain. We analyzed whether addition of (es)omeprazole to acenocoumarol or phenprocoumon increases the international normalized ratio (INR) levels and the risk of overanticoagulation. METHODS: We analyzed all hospital admissions in four teaching hospitals. Patients who used coumarins and pantoprazole or (es)omeprazole simultaneously for at least four consecutive days were included in the study. We analyzed the highest INR level and whether patients had an INR level above six. We compared patients using omeprazole or esomeprazole with patients using pantoprazole, because for pantoprazole, no interaction has been reported. RESULTS: We analyzed 5747 admissions with 4540 patients using one of the drug combinations. For acenocoumarol (4578 admissions), no significant differences were found between users of esomeprazole, omeprazole, and pantoprazole. For phenprocoumon (1169 admissions), the highest INR measured was significantly higher in users of esomeprazole than in users of pantoprazole (4.7 versus 4.3; p = 0.035). No significant difference was found with omeprazole versus pantoprazole (4.3 versus 4.3; p = 0.66). A non-significant association was found between the esomeprazole dose and the highest INR level (p = 0.055). The risk of an INR above six did not differ significantly between esomeprazole and pantoprazole (27.7 % versus 22.9 %; p = 0.34). CONCLUSIONS: The use of esomeprazole simultaneously with phenprocoumon during hospital admissions might increase the anticoagulant effect. The clinical relevance seems to be limited, because no statistically significant increased risk of overanticoagulation was found.

Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects.

BACKGROUND: Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature. METHODS AND RESULTS: Platelet activation (ß-thromboglobulin [ß-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood ß-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of ß-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state. CONCLUSION: A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.

Oral anticoagulation and vitamin K deficiency.

A 61-year old woman with atrial fibrillation developed macrohaematuria during anticoagulant treatment with a direct oral factor Xa inhibitor for stroke prevention. Abnormal results of coagulation assays were first interpreted as an effect of the anticoagulant. However, upon further testing diagnosis of vitamin K deficiency was established. After vitamin K supplementation, coagulation tests normalized and macrohaematuria disappeared. Treatment with broad spectrum antibiotics for urinary tract infection was finally established as a rare cause for vitamin K deficiency in the patient.

Dietary vitamin K intake and anticoagulation in elderly patients.

PURPOSE OF REVIEW: Vitamin K is an essential co-factor for the synthesis of several coagulation factors. Oral anticoagulants competitively inhibit enzymes that participate in vitamin K metabolism. The purpose of this review is to evaluate the potential interaction of dietary vitamin K and coagulation stability, particularly in the elderly patient. RECENT FINDINGS: Recent prospective evidences suggest that dietary vitamin K plays an essential role in anticoagulation stability. Vitamin K intake of more than 250 microg/day was shown to decrease warfarin sensitivity in anticoagulated patients consuming regular diets. In a randomized crossover study, brief periods of changes on vitamin K intake also had significant effects on coagulation parameters. Patients that were allocated to an 80% decrease of intake increased International Normalized Ratio (INR) by almost 30% 7 days after the intervention. Similarly, it was estimated by dietary records that for each increase in 100 microg of vitamin K intake, the INR would be reduced by 0.2. A recent study also demonstrated that over-the-counter multivitamin supplements contain enough vitamin K1 to significantly alter coagulation parameters. SUMMARY: Contemporary data strengthen the concept that the interaction between dietary vitamin K and coumarin derivatives is clinically relevant and plays a major role in INR fluctuations in chronic anticoagulated patients.

[Partial resistance to acenocoumarol and phenprocoumon caused by enzyme polymorphism]. / Partiële acenocoumarol- en fenprocoumonresistentie door enzympolymorfisme.

A 78-year-old man was treated with coumarin derivatives following myocardial infarction. The international normalised ratio was not increased by using standard loading doses and dose adjustments for acenocoumarol and phenprocoumon. The desired level of anticoagulation was achieved with a high dosage of phenprocoumon (18-21 mg daily). This dose was associated with a phenprocoumon serum concentration that was ten times higher than the normal therapeutic concentration. The serum concentration of vitamin K1 was low. After exclusion of alternative causes, we concluded that the exceptionally high dose of phenprocoumon needed was due to partial resistance to coumarin derivatives. Partial resistance is related to a polymorphism of the gene coding for the enzyme vitamin K epoxide reductase. The patient was successfully treated with chronic high-dose phenprocoumon. Resistance to coumarin derivatives caused by a congenital polymorphism in the vitamin K reductase gene is a rare phenomenon. Resistance is seldom absolute. The desired anticoagulation effect can be achieved with doses that are 10-20 times higher than standard doses. Phenprocoumon is advantageous in this situation because it requires fewer tablets than acenocoumarol. Determination of serum concentrations of acenocoumarol and phenprocoumon can be used to exclude other causes of treatment resistance.

Heart transplantation under coumarin therapy: friend or foe?

Thirty-six patients were included in a retrospective study of the effect of pre-operative anticoagulant therapy on peri-operative blood loss and haemostatic changes after heart transplantation. Eleven patients (group H) had received intravenous heparin for at least 3 weeks before cardiac transplantation. Twelve patients (group P) had been transplanted when fully anticoagulated with phenprocoumon. A control group of 13 patients (group C) had undergone bypass grafting of their coronary arteries with no pre-operative anticoagulant therapy. Post-operative drainage from the chest drains was 700 ml (median) in group H, 425 ml in group P, and 360 ml in group C (group H vs. group C: P < 0.05). After heparinization for cardiopulmonary bypass, activated clotting time was 462 s (median) in group H, 1500 s in group P, and 727 s in group C (P < 0.003 vs. groups H and P). Post-operatively, patients in group P were given more units of fresh frozen plasma (median 2.5 units; P < 0.01), prothrombin complex concentrate (median 1000 I.U.; P < 0.05) and vitamin K (median 10 mg; P < 0.05) than groups H and C. Heart transplantation under full phenprocoumon therapy does not increase the likelihood of complications caused by peri-operative bleeding.