Coumarin Therapy Research Articles

A-335 Evaluation of the Next Generation i-STAT® Point of Care Prothrombin Time Test

Abstract Background The i-STAT® PTplus cartridge contains a point of care prothrombin time (PT) test. The purpose of this study was to assess the performance of the i-STAT PTplus cartridge compared to other commercially available PT tests namely, Dade® Innovin® on the Sysmex® CS-2500 and the Roche CoaguChek®. The i-STAT® PTplus cartridge is a point of care whole blood test for the determination of prothrombin time. It is used to aid in the monitoring of patients receiving anticoagulant therapy with coumarin derivatives. Methods Venous and capillary whole blood specimens were prospectively collected with IRB approved informed consent from 222 subjects undergoing coumarin therapy and from subjects who were not on anticoagulant therapy at three clinical sites to span the reportable range of 0.8 - 8.0 INR. Both venous and capillary whole blood specimens were tested in duplicate on the i-STAT 1 Wireless Analyzer and were tested in singlicate on the Roche CoaguChek® device. Plasma from a citrated venous blood specimen obtained from the same subjects was tested in duplicate on the Sysmex® CS-2500 instrument. Results The Passing-Bablok regression results in the table below demonstrate international normalized ratio (INR) in the first replicate of the i-STAT PTplus cartridge versus the first replicate comparative device for venous and capillary whole blood. Conclusions This study demonstrates that the i-STAT® PTplus cartridge has good agreement to both laboratory and point of care commercially available PT tests when tested with venous and capillary whole blood from subjects not on anticoagulant therapy and subjects receiving coumarin therapy. The studies were funded by Abbott Laboratories.

Significance of the multifunctional protein C system research in the treatment of patients with indirect anticoagulants (literature review)

The multifunctional protein C system regulates both hemostasis and the immune system in response to vascular and inflammatory damage, inhibits thrombinogenesis at an early stage of clotting. A decrease in protein C levels in clinical practice may be associated with vitamin K deficiency, as well as with coumarin therapy. Prolonged use of indirect anticoagulants may be accompanied by a decrease in protein C levels and contribute to the development of rebound thrombosis and thromboembolism. The depth of violations of the protein C system indicates the activation of the microthrombosis process and may affect the outcome of treatment of surgical patients.

The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance

Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.

The association of high-normal international-normalized-ratio (INR) with mortality in patients referred for coronary angiography.

AimsThe international-normalized-ratio (INR) is typically used to monitor patients on warfarin or related oral anticoagulant therapy. The aim of our study was to investigate the association of the INR with mortality in coronary artery disease (CAD) patients not on oral anticoagulant therapy.Methods and resultsBetween 1997 to 2000 the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study enrolled 3316 patients of German ancestry that had been referred for coronary angiography. We excluded patients on coumarin therapy (n = 222) and patients with an INR more than 5 standard deviations (SD) away from the mean (n = 30). During a median follow-up of 9.9 years, 884 patients died, 547 patients from cardiovascular causes. After adjustment for cardiovascular risk factors the INR was associated with all-cause mortality in all patients and the CAD positive group with HRs (95% CI) of 1.14(1.07–1.21) and 1.16(1.09–1.23) per 1-SD increase, respectively. Adjustment for NT-proBNP rendered the association insignificant.ConclusionIn LURIC, the INR was positively associated with mortality in patients with prevalent CAD not on oral anticoagulant therapy as well as in patients without CAD. Adjustment for NT-proBNP abolished the association suggesting clinical or subclinical heart failure strongly contributing to increased INR and higher mortality.

Resolving DOAC interference on aPTT, PT, and lupus anticoagulant testing by the use of activated carbon

BackgroundDirect oral anticoagulants (DOACs) affect laboratory coagulations tests. Activated carbon (AC) can be used for adsorption of DOACs during acute human intoxications. ObjectivesThis study evaluates whether AC can also be used to resolve DOAC interference on in vitro clotting tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], and lupus anticoagulant [LA] assays). Patients/MethodsInterference on PT, aPTT, Liquid anti‐FXa, DTI, and LA screening/confirmation (SCT and dRVVT) was determined by spiking citrated plasma from 5 adult controls with 0, 20, 40, 80, 120, or 160 mg/mL AC. DOAC concentrations, PT, and aPTT were compared before and after AC addition to citrated plasma from patients receiving DOACs (n = 29), low molecular weight heparin (n = 10), and coumarin (n = 10) therapy. Samples from 69 LA screened patients were compared before and after AC addition. ResultsA concentration of 20 mg/mL AC had the lowest interference and was selected for further experiments. After AC addition, all DOAC concentrations were below the limit of quantification in the 29 treated patients, except for 2 apixaban samples. AC removed DOAC interference on PT and aPTT but had no impact on results obtained during coumarin or low molecular weight heparin therapy. Of 15 LA samples with interference resulting from DOAC therapy, 14 samples became negative and 1 positive after AC addition. Interference from coumarin therapy was not resolved. All 19 LA negative samples remained negative. AC treatment of the negative pooled plasma was required to avoid false‐negative LA results in 21 known LA‐positive samples. ConclusionsAC selectively removes DOAC interference on PT, aPTT, and LA assays.

Tailored on demand anti-coagulant dosing: An in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms

Coumarin therapy has been associated with high levels of inter- and intra-individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using in-vitro and in-vivo models. Sodium warfarin loaded filaments were compounded using hot melt extrusion (HME) and further fabricated via fused deposition modelling (FDM) 3D printing to produce capsular-ovoid-shaped dosage forms loaded at 200 or 400 µg dose. The solid dosage forms and comparator warfarin aqueous solutions were administered by oral gavage to Sprague–Dawley rats. A novel UV imaging approach indicated that the erosion of the methacrylate matrix was at a rate of 16.4 and 15.2 µm/min for horizontal and vertical planes respectively. In vivo, 3D printed forms were as proportionately effective as their comparative solution form in doubling plasma exposure following a doubling of warfarin dose (184% versus 192% respectively). The 3D printed ovoids showed a lower Cmax of warfarin (1.51 and 3.33 mg/mL versus 2.5 and 6.44 mg/mL) and a longer Tmax (6 and 3.7 versus 4 and 1.5 h) in comparison to liquid formulation. This work demonstrates for the first time in vivo, the potential of FDM 3D printing to produce a tailored specific dosage form and to accurately titrate coumarin dose response to an individual patient.

The efficacy and safety of edoxaban in non-valvular atrial fibrillation

The significantly increased incidence of stroke and systemic embolisation caused by atrial fibrillation can be prevented by adequately adjusted anticoagulant therapy. Vitamin K antagonists effectively decrease the risk of thromboembolic events but this effect is influenced by many factors. The development of the new direct oral anticoagulant drugs (DOAC) in the last few years provided new opportunities for us to choose the suitable anticoagulant therapy. According to the results of the ENGAGE AF-TIMI 48 and ENSURE-AF multicenter, randomized trials, edoxaban, the recently introduced DOAC is equally effective as the traditional coumarin therapy, nevertheless, it ensures more tolerable anticoagulation for patients suffering from non-valvular atrial fibrillation. Orv Hetil. 2018; 159(12): 466-469.

Evidence for periprocedural antiplatelet therapy, heparinization and bridging of coumarin therapy in carotid revascularization.

Thromboembolism prevention is a crucial factor determining both the natural outcome and outcome of intervention of stenotic atherosclerotic carotid artery pathology. Roughly 80% of all natural course cerebral ischemic events are caused by thromboembolism, versus 20% due to hemodynamic insufficiency. The risk of periprocedural cerebral (micro-) thromboembolization during carotid revascularization is considered to be even higher, with a higher rate in carotid artery stenting (CAS) as compared to carotid endarterectomy (CEA). Guidelines on CEA and CAS are unanimous in advising perioperative continuation of antiplatelet therapy (APT) for all patients to prevent thromboembolization without specification of the type of APT. Recommendations on dual antiplatelet (DAPT) therapy are inconsistent. Bridging vitamin K antagonists (VKA) perioperative with unfractionated heparin (UFH) or low-molecular weight heparins (LMWHs) might not be necessary for CAS, while CEA-specific data is lacking. No data are available on the use and position of direct-acting oral anticoagulants (DOACs) for CEA or CAS. Guidelines on treatment of carotid artery disease currently do not provide information on perioperative heparinization. There are several monitoring tools to detect perioperative micro-embolic signals during intervention or new cerebral white matter lesions following CEA or CAS. Transcranial Doppler ultrasonography (TDU) and diffusion weighed imaging (DWI) might be used to assess these (secondary) outcome measurements. The use of platelet function testing (PFT) to tailor APT might contribute to finding the therapeutic place of stronger APT and new APT regimen. Periprocedural antiplatelet and anticoagulation therapy for carotid revascularization still lacks solid evidence and guidelines do not yet cover the full spectrum of anticoagulants and procedural steps. This review aims to cover and discuss the full spectrum of available antiplatelet and anticoagulant drugs and therapies available for thromboembolism prevention during all crucial steps of revascularization and specify the need to know topics to be addressed in future research.

The COAG and EU-PACT trials: what is the clinical benefit of pharmacogenetic-guided coumarin dosing during therapy initiation?

Coumarin derivates are oral anticoagulants commonly prescribed for treatment and prevention of thromboembolism. Due to a small therapeutic index and large inter- and intrapatient differences in dose requirements, treatment with coumarins is challenging, particularly in its starting phase. Extensive evidence suggests that common genetic variants in CYP2C9 and VKORC1 genes together with a number of clinical factors are important determinants of the coumarin dose variability. Pharmacogenetic algorithms comprising both genetic and non-genetic factors were developed to improve the safety of coumarin therapy initiation. Recently, three randomized controlled trials (the COAG and the EU-PACT trials) on pharmacogenetic dosing of warfarin, acenocoumarol and phenprocoumon were published. In these trials different coumarin dosing strategies were compared to investigate whether or not pharmacogenetic testing could be beneficial for coumarin management. The purpose of this review was to present and discuss the design and results of these studies within the context of previously published randomized controlled trials and to address the issues surrounding the incorporation of coumarin pharmacogenetic testing into clinical practice.

Late onset of pulmonary cement embolism after a regular vertebroplasy. A clinical documentation

Abstract Vertebroplasty is a new minimal-invasive procedure for the treatment of painful vertebral fractures. The risk of a pulmonary embolism ranges from 3.5 to 23% for osteoporotic fractures. However, data about the incidence and treatment strategies of pulmonary cement embolisms (PCE) are limited. We report a case of a patient with symptomatic pulmonary cement embolism after the vertebroplasty. The diagnosis was confirmed by means of CT- scan. In cases of asymptomatic patients with peripheral PCE we recommend no treatment besides clinical follow-up. In our case of symptomatic embolisms, we recommend to proceed according to the guidelines regarding the treatment of thrombotic pulmonary embolisms, which includes initial heparinization and a following 6-month coumarin therapy.

Rationalized DNA sequencing-based protocol for genotyping patients receiving coumarin therapy

During the last decade genetic factors affecting coumarin therapy have been extensively investigated. The most important genes appear to be CYP2C9 and VKORC1, and different studies have shown that DNA testing can dramatically improve the safety and effectiveness of the therapy. However, the implementation of pharmacogenetic testing in everyday practice is still not a reality. Facilities and ability to get results before the start of therapy are very important. The implementation of specific methodology and equipment for particular type of diagnostics can represent a serious, even impossible, financial hurdle to overcome (especially in developing countries). For this reason, the use of every tool that contributes to rationalization of the existing methods can be a considerable asset. Therefore, we set the goal to rationalize our current DNA sequencing based protocol for analysis of the VKORC1 c.-1639G> A, CYP2C9*2 and CYP2C9*3 variant alleles, in order to obtain shorter and easier procedure. Simplification of the protocol was achieved by setting up multiplex PCR and omitting DNA extraction. This rationalization of the existing DNA sequencing based procedure allows getting results in 12 hours. The new protocol was tested on 118 samples. Obtained results have shown full accordance to those obtained with previous, non-modified protocol. Therefore, given the circumstances, we consider that protocol for pharmocogenetic testing should be made more accessible – both to doctors and patients. It is one of the prerequisites in order to make genotyping prior to the therapy common practice.

Is sodium thiosulfate a therapeutic option for non-uremic calciphylaxis?

Introduction: Non­uremic calciphylaxis, a rare disorder with high mortality, is associated with severe calcifications of the media of arterioles which cause vascular occlusion and tissue necrosis. Case Report: A non­uremic calciphylaxis of the lower limb, possibly caused by coumarin therapy for atrial fibrillation. Treatment consisting of coumarin avoidance, vitamin K supplementation and thrice weekly infusion of 20 g of sodium thiosulfate for three weeks led to complete healing of the leg ulcers. Conclusion: Sodium thiosulfate produces a considerable sodium load and may induce a decrease in serum calcium, potassium and phosphate levels as well as an increase in the anion gap. We suggest that sodium thiosulfate is effective in the treatment of non­uremic calciphylaxis, but its use requires monitoring of electrolytes, acid­ base and volume status. Based on previous studies of sodium thiosulfate pharmacokinetics in individuals with normal renal function, which showed rapid excretion by the kidneys, application as a slow infusion over several hours is recommended in order to enhance its efficacy and avoid unwanted side effects.

Discontinuation of anticoagulant care during admission to a psychiatric hospital

Continuation of coumarin therapy is important to prevent thromboembolic events. Continuation of medication, unrelated to the reason for hospital admission, may be at risk due to the patient's psychiatric status and the involvement of several physicians in patient care. We performed a retrospective follow-up study of users of orally administered anticoagulants who were admitted to a psychiatric hospital. Information on patient characteristics, anticoagulant use, and International Normalized Ratio (INR) measurements was collected. Discontinuation of anticoagulant care was defined as no anticoagulant dispensing during the first 7 days of hospitalization and/or no INR measurement during hospitalization. Relative risks (RR) of discontinuation, overall and stratified by patient characteristics, was estimated using Cox regression analysis. Of 111 patients, 24.3 % had their anticoagulant care discontinued. For 17.1 %, no anticoagulant was dispensed during the first week, and 13.5 % had no INR measurement during hospitalization. Admission to a psychiatric hospital leads to discontinuation of anticoagulant care in 24.3 % of patients, with highest risk of discontinuation in patients admitted to nonpsychogeriatric wards. More research is needed to evaluate the clinical impact of this finding.

Antithrombotic Options for Atrial Fibrillation in 2012

Atrial fibrillation (AF) is a common arrhythmia in clinical practice. An important component of the management of patients with AF involves prevention of thromboembolism and stroke. Coumarins, such as warfarin had been the only available oral antithrombotic agent for prevention of thromboembolism for many decades. Following intestinal absorption, coumarins inhibit multiple steps of the clotting cascade that leads to inhibition of coagulation factors II, VII, IX and X. In addition to delayed and variable inhibition of coagulation, coumarin therapy has a narrow therapeutic window for optimal balance of risk and benefit, which requires regular assessment of the international normalized ratio (INR) to monitor coagulation. A quest for safer, more effective therapies that do not need monitoring has led to the development of dabigatran, rivaroxaban, and apixaban. In this article, we review these newer antithrombotic agents and discuss role of these drugs in clinical practice.

Rolle der Vitamin-K-Antagonisten aus Sicht des Hepatologen

Vitamin K antagonists are often used as oral anticoagulants for primary and secondary prevention of thromboembolic events. Vitamin K antagonists induce an anticoagulant effect by interfering with the vitamin K metabolism in the liver. Well-known complications are bleeding events and skin necrosis. Recent data indicate increasing numbers of cases with hepatic complications due to vitamin K antagonists ranging from mild hepatopathy to acute liver failure with high mortality. Hepatotoxicity is usually developed after a few months of latency, which is associated with unspecific symptoms, jaundice, elevated transaminase levels as well as cholestatic enzymes. Hepatotoxicity due to vitamin K antagonists is seldom; however, it should be considered in cases of elevated liver enzymes. In this case coumarin therapy should be discontinued. Caution is needed when changing to another coumarin derivative because cross-reactivity has been described.

Palpable nekrotisierende Purpura unter Cumarin-Therapie - Case Report und Literatur-Review

We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on the left thigh, which appeared without trauma. The disease arrived during longterm coumarin therapy because of a deep vein thrombosis and an antiphospholipid syndrome. After consideration of the differential diagnoses and due to the typical clinical picture we made the diagnosis of coumarin necrosis. We review the clinical and therapeutic features for this rare complication.

Coumarins and survival in incident dialysis patients

The benefit and risk of oral anticoagulation in dialysis patients are debated controversially. We prospectively followed 235 dialysis patients of the INVOR Study (Study of Incident Dialysis Patients in Vorarlberg) for up to 7 years and analysed the prevalence and incidence of atrial fibrillation (AF) and the impact of coumarin therapy on survival. Oral anticoagulation was monitored frequently. A total of 748 person-years were recorded with a median follow-up of 2.84 years. Twelve patients (5.1%) had AF at the start of dialysis. During follow-up, 40 patients (17.0%) developed AF, representing an incidence of 5.85 per 100 person-years. AF was positively associated with mortality (P = 0.004). Forty-six (19.6%) of the 235 patients were treated with coumarins. The majority (93.7%) had a clear indication for oral anticoagulation. In 65% of our patients, AF was the indication for coumarins. Patients without coumarins and without AF represented our reference group. The mortality risk of the coumarin-treated patients with AF or an alternative indication for coumarins was slightly lower compared to the reference group [hazard ratio (HR) 95% confidence interval (CI): 0.80 (0.28-2.29), P = 0.679 and 0.42 (0.16-1.10), P = 0.078, respectively]. No patient under sufficient oral anticoagulation experienced a stroke or a fatal bleeding event. Patients with AF and a contraindication for coumarins had a significantly higher mortality risk compared to the reference group [HR (95% CI): 3.90 (2.16-7.04), P < 0.001]. Our data suggest that coumarins might be less harmful than previously anticipated when clearly indicated and closely monitored.

A severe renal bleeding as a complication of coumarin therapy in Behçet's disease

Behçet's disease is a systemic inflammatory disease, which predisposes patients to venous or arterial thrombosis. We report a case of 41-year-old patient who presented for several years with recurrent fevers, arthralgias, episodes of skin eruptions and recurrent bilateral deep venous ileofemoral thromboses, extending into the inferior vena cava, despite the oral anticoagulant therapy. Additionally, he also reported recurrent aphthous oral and genital lesions, and eye problems. A laboratory picture of chronic inflammation, normocytic anaemia and a finding of lupus anticoagulant/antiphospholipid antibodies were observed. PET raised a high suspicion of vasculitic PTT-lupus anticoagulant process, involving the large vessels. During an anticoagulant therapy by warfarin (dose in upper limit of therapeutic range), the left kidney had to be removed because of acute retroperitoneal haemorrhage. On histologic examination, the picture of nephritis was described. A detailed retrospective reevaluation of complex history as well as other clinical findings strongly raised the suspicion of a systemic vasculitic syndrome, such as Behçet's disease, accompanied by antiphospholipid syndrome. The patient responded well to the combination of colchicine and anticoagulant therapy by low-molecular-weight heparin. The episodes of fever, skin eruptions and other symptoms disappeared. We assume that this is a case of an unusual course of Behçet's disease presenting with a rare kidney involvement. Kidney disorder complicated the oral anticoagulant therapy for recurrent venous thromboses and led to the excessive renal bleeding, requiring nephrectomy. Recognition that nephritis is associated with Behçet's disease may be useful to prevent severe renal bleeding in relation to anticoagulant therapy.

A large family from Argentina with Prekallikrein deficiency due to a compound heterozygosis (T insertion in intron 7 and Asp558Glu in exon 15): Prekallikrein Cordoba

A family with prekallikrein deficiency (PK) from Argentina was investigated by molecular biology techniques. Parents were not consanguineous. Propositus had prolonged PTT but normal PT. Degree of prolongation of aPTT varied with the activator and showed shortening on prolonged incubation. Defect was fully corrected by normal, FXII, FXI, or high molecular weight kininogen (HMWK) deficient plasmas. Prekallikrein activity was 4% whereas prekallikrein antigen was normal and had a normal electrophoretic mobility. Propositus presented a thigh deep vein thrombosis. He was treated with LMWH and coumarin together with supportive stockings. An affected brother of the propositus had two myocardial infarctions and was on coumarin therapy. Other family members never showed thrombotic events. No bleeding tendency was ever noted. Children of probands showed PK activity of 50% of normal whereas antigen was normal.

Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate

Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two-phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min(-1) with a median of 7.5 mL min(-1). Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min(-1) (95% confidence interval, 1.0-4.3 mL min(-1)) among patients receiving Beriplex P/N volumes > or =80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness.