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Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations and unexpected deaths. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be important therapeutic agents. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to determine whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 μg/kg) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of AP was assessed immediately after the last dose of cerulein, as well as at days 1, 2, 3, 5, and 10 after AP induction. Treatment with warfarin dose-dependently increased international normalized ratio (INR) and attenuated the severity of pancreatitis in histological examination and accelerated pancreatic recovery. These effects were accompanied with a faster reduction in the AP-evoked increase in serum activity of amylase and lipase, the serum concentration of pro-inflammatory interleukin-1β, and the plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight (an index of pancreatic edema) and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 μg/kg. We conclude that treatment with warfarin accelerated regeneration of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.

Aim: Healthcare resources usage and costs associated to nonvalvular atrial fibrillation (NVAF) were analyzed in Spain. Methods: This is an observational and retrospective study on patients with NVAF who started their treatment with apixaban or acenocoumarol between 1 January 2015 and 31 December 2017. Results: 2160 patients treated with apixaban were paired (1:1) with patients treated with acenocoumarol (propensity score matching). Apixaban reduced the incidence of strokes and systemic embolisms, minor and major bleedings and deaths, versus acenocoumarol. Apixaban led to reductions of 80, 55 and 43% in costs related to nursing visits, hospitalizations, and emergency visits, respectively, leading to annual cost savings of €274/patient, from the perspective of society. Conclusion: Our results suggested that apixaban is a cost-effective alternative for patients with NVAF.

Effective prevention of thromboembolism is essential for patients with mechanical prosthetic heart valves. For this group of patients, vitamin K antagonists (VKAs) remain the drug group of choice despite the widespread use of new anticoagulants in other diseases. As a consequence, warfarin resistance remains a serious challenge for physicians. The current report describes a 65-year-old male patient that had a mechanical prosthetic aortic valve implanted due to severe aortic insufficiency after infective endocarditis. Despite consistent increases in his warfarin dose, the level of international normalized ratio (INR) remained very low. The patient was considered to have warfarin resistance. Warfarin was successfully replaced by another VKA, acenocoumarol, which resulted in a stable INR observed over 1 year of follow-up. Achieving the target INR in patients with mechanical prosthetic heart valves using VKAs is the main goal of thromboprophylaxis. Although the genetic changes that cause warfarin resistance are understood, the options to overcome these pharmacogenetic issues remain limited. Based on the success with this current patient, physicians with similar patients with warfarin resistance might wish to consider replacing warfarin with acenocoumarol.

Introduction: The use of vitamin K antagonists (VKAs) in non-valvular atrial fibrillation (NVAF) is complicated due to the narrow therapeutic margin they present and their unpredictable dose-response relationship. Most studies are based on warfarin, with the results being extrapolated to acenocoumarol. However, studies comparing the two treatments in terms of the degree of anticoagulation control are scarce, justifying the present study. Main factors associated with poor control of time in therapeutic range (TTR) of anticoagulated patients are also studied. Methods: Cross-sectional study, with real-world data from patients treated in primary care (PC). Data were obtained from the System for the Improvement of Research in PC (SIDIAP) database, covering 60,978 NVAF-anticoagulated patients from 287 PC centres in 2018. Descriptive statistics were derived, and odds ratios were estimated by multivariate logistic regression. Results: 41,430 patients were considered: 93% were being treated with acenocoumarol and 7% with warfarin. There was no difference in poor control of TTR between the two types of VKA treatment, acenocoumarol and warfarin (38.9 vs. 38.4; p = 0.610). Poor anticoagulation control was mainly associated with advanced alcoholism (OR = 1.38), liver failure (OR = 1.37) and intracranial haemorrhage (OR = 1.35) as well as female sex, age < 60 years, cardiovascular history, diabetes mellitus and other variables. Conclusions: There is no association between poor anticoagulation control and the type of VKA treatment administered. Factors associated with poor control of TTR must be considered in clinical practice to improve control and decision-making.

Vitamin K antagonists are indicated for the thromboprophylaxis in patients with mechanical prosthetic heart valves (MPHV). However, it is unclear whether some differences between acenocoumarol and warfarin in terms of anticoagulation quality do exist. We included 2111 MPHV patients included in the nationwide PLECTRUM registry. We evaluated anticoagulation quality by the time in therapeutic range (TiTR). Factors associated with acenocoumarol use and with low TiTR were investigated by multivariable logistic regression analysis. Mean age was 56.8 ± 12.3 years; 44.6% of patients were women and 395 patients were on acenocoumarol. A multivariable logistic regression analysis showed that patients on acenocoumarol had more comorbidities (i.e., ≥3, odds ratio (OR) 1.443, 95% confidence interval (CI) 1.081-1.927, p = 0.013). The mean TiTR was lower in the acenocoumarol than in the warfarin group (56.1 ± 19.2% vs. 61.6 ± 19.4%, p < 0.001). A higher prevalence of TiTR (<60%, <65%, or <70%) was found in acenocoumarol users than in warfarin ones ( p < 0.001 for all comparisons). Acenocoumarol use was associated with low TiTR regardless of the cutoff used at multivariable analysis. A lower TiTR on acenocoumarol was found in all subgroups of patients analyzed according to sex, hypertension, diabetes, age, valve site, atrial fibrillation, and INR range. In conclusion, anticoagulation quality was consistently lower in MPHV patients on acenocoumarol compared to those on warfarin.

Background: Anticoagulant therapy is used for stroke prevention and proved to be effective and safe in the long term. The study aims to analyse the cost-effectiveness relationship of using of direct-acting oral anticoagulants vs vitamin K antagonists to prevent ischaemic stroke in patients with nonvalvular atrial fibrillation, including all the active ingredients marketed in Spain, prescribed for 2 years in the Primary Care service of the Institut Català de la Salut., Methods: Population-based cohort study, in which the cost of the 2 treatment groups will be evaluated. Direct costs (pharmacy, primary care, emergency and hospitalization) and indirect costs (lost productivity) will be included from a social perspective. Effectiveness (assessed as the occurrence of a health event, the 1 of primary interest being stroke) will be determined, with a 2-year time horizon and a 3% discount rate. The average cost of the 2 groups of drugs will be compared using a regression model to determine the factors with the greatest influence on determining costs. We will carry out a univariate ('one-way') deterministic sensitivity analysis., Discussion: We hope to provide relevant information about direct and indirect costs of oral anticoagulants, which, together with aspects of effectiveness and safety, could help shape the consensual decision-making of evaluating bodies.

Background: Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control., Aims: We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability., Methods and Results: In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2-3, 269 patients in target range 2-3.5 and 98 patients in target range 2.5-3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers' TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2-3, 2-3.5 and 2.5-3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers' INRs were much more stable than non-switchers'., Conclusion: Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The authors report the following potential conflicts of interest: J.H.A. van Miert has nothing to disclose. N.J.G.M. Veeger has nothing to disclose. A.J. ten Cate-Hoek has nothing to disclose. M. Piersma-Wichers reports travel support from LEO pharma, travel and conference support from Pfizer, and a research grant from Federatie van Nederlandse Trombosediensten, outside the submitted work. K. Meijer reports travel support from Baxter; grants, travel support and speaker fees from Bayer; grants and speaker fees from Sanquin; grants from Pfizer; speaker fees from Boehringer Ingelheim; speaker fees from BMS; speaker fees from Aspen; consulting fees from Uniqure; grants from Federatie van Nederlandse Trombosediensten; all outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aim: To compare the risk of stroke, systemic thromboembolism and bleeding, in patients initiating apixaban or acenocoumarol for the treatment of nonvalvular atrial fibrillation. Methods: An observational, retrospective study was performed using medical records of patients who initiated apixaban or acenocoumarol between 2015 and 2017. Propensity score matching was used to match patients; stroke, systemic thromboembolism, major and minor bleeding events were compared between the matched patients.  Results: Patients who were prescribed apixaban had a lower rate of systemic embolism/stroke (hazard ratio [HR] = 0.54; 95% CI: 0.38-0.78; p = 0.001), minor bleeding (HR = 0.64; 95% CI: 0.52-0.79; p < 0.001) and major bleeding (HR = 0.51; 95% CI: 0.37-0.72; p < 0.001). Conclusion: Patients prescribed apixaban for the treatment of nonvalvular atrial fibrillation had lower rates of thromboembolic events and minor/major bleeding than patients on acenocoumarol.

Aims: Bridging anticoagulation in atrial fibrillation (AF) patients who need to interrupt vitamin K antagonists for procedures is a clinical dilemma. Currently, guidelines recommend clinicians to take the stroke and bleeding risk into consideration, but no clear thresholds are advised. To aid clinical decision making, we aimed to develop a model in which periprocedural bridging therapy is compared with withholding anticoagulation in AF patients, for several bleeding and stroke risk groups., Methods and Results: A model was developed to simulate both a bridge and a non-bridge cohort, using simulated international normalized ratio (INR) values for patients on warfarin, acenocoumarol, and phenprocoumon. For both clinical strategies, stroke and bleeding risks were included and outcomes were stratified by CHA2DS2-VASc or CHADS2 and HAS-BLED groups. Quality-adjusted life expectancy was the main outcome considered. Our analyses show bridging to only be beneficial for patients with HAS-BLED scores equal or lower to 2 and with CHA2DS2-VASc scores of 6 or higher. For patients using acenocoumarol bridging may be beneficial starting at a CHA2DS2-VASc score of 7. Post-procedural time to therapeutic INR has a significant influence on the results: no significant benefit of bridging was found for patients reaching therapeutic INR values within 5 days., Conclusion: When deciding whether to bridge anticoagulation, clinicians should consider the patient's individual stroke and bleeding risk, while also considering the patient's post-procedural INR management. In practice, only a small subset of patients is expected to benefit from bridging anticoagulation treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice.

Unfavorable fibrin clot features have been observed in patients with venous thromboembolism (VTE). We investigated whether rivaroxaban, a direct factor Xa inhibitor, and vitamin K antagonists (VKAs) can improve plasma clot viscoelastic properties. We studied four age- and sex-matched groups: 25 healthy controls, 15 VTE patients taking rivaroxaban 20 mg/day (blood concentration, 145 (67 - 217) ng/ml), 15 VTE patients taking VKA (INR: 2 - 3), and 15 VTE patients who stopped oral anticoagulant therapy (OAT). Using a hybrid rheometier the storage (G') and loss (G") moduli were evaluated in citrated plasma after addition of 5 pmol/l tissue factor. Fiber thickness within clots was assessed using scanning electron microscopy. Higher G' but not G" was observed for VTE patients taking rivaroxaban (+34%; post hoc, P = 0.029) compared to controls. As reflected by lower G' and G", patients taking rivaroxaban (-19% and -30%; post hoc, P = 0.0013 and P < 0.0001, respectively) formed less stiff and viscous clots compared to VTE patients after OAT withdrawal, also after adjustment for fibrinogen. VTE patients treated with rivaroxaban and VKA had similar clot viscoelastic properties (post hoc, P = 0.85 for G' and P = 0.29 for G"). G' and G" correlated with plasma rivaroxaban concentrations (r = -0.67, P = 0.005 and r = -0.59, P = 0.021, respectively), and the time from the last dose of rivaroxaban intake (r = 0.59, P = 0.02 and r = 0.58, P = 0.022, respectively). G' and G" showed no association with INR in patients on VKAs. G' or G" were not associated with fibrin diameter on scanning electron microscopy images in either group. Our preliminary study shows that both rivaroxaban and VKA improve clot viscoelastic properties in VTE patients, which might contribute to their antithrombotic effects. G' and G" may reflect specific clot physical features, beyond key plasma clot characteristics, which highlights benefits from comprehensive plasma clot analysis in patients with thrombotic diseases.

Background: Non-operative management (NOM) may be particularly challenging in patients receiving synchronous antithrombotic therapy (AT). The current study examined the feasibility of NOM in patients under AT who sustained blunt splenic or hepatic injuries., Methods: We analyzed the results of a 5-year (2010-2014) pre-decided treatment protocol, including 15 patients under AT who were treated for splenic and/or hepatic injuries at our institution. The antithrombotic therapy consisted of acenocoumarol 4 mg, acetylsalicylic acid 100 mg and clopidogrel 75 mg. Vitamin K (Vit K), Fresh frozen plasma (FFP) and Prothrombin Complex Concentrate (PCC) were transfused to patients receiving anticoagulant therapy, while platelets (PLTs) were given to patients under antiplatelet therapy if their level was excessively low. The organ injury grading scale, injury severity score (ISS), the need for blood transfusion and intensive care unit (ICU)/ high dependency unit (HDU) admission, morbidity, mortality and duration of hospital stay were also recorded., Results: Ten patients fulfilled the criteria for NOM and were treated accordingly. No conversion to operative management (OM) was required (success rate 100%). Five patients were managed surgically due to hemodynamic instability and/or signs of peritonitis. Reversal of AT was attempted in all cases., Conclusions: Hemodynamically stable patients under AT with blunt hepatic or splenic injuries (grade ≤ III) and no signs of peritonitis, may be good candidates for NOM, despite their bleeding tendency. The type of AT does not seem to influence the final outcome. Reversal of AT should be stratified individually., Key Words: Antithrombotic therapy, Hemodynamic stability, Non-operative management.

Background: Anticoagulation with vitamin K antagonists continues to be a challenging task given the difficulty of achieving a correct time in therapeutic range (TTR). The SAMeTT 2 R 2 score has been proposed to identify patients that will be good responders. In this study we aimed to analyse clinical and genetic factors involved in a correct level of anticoagulation in patients with atrial fibrillation and thereby potentially improve the diagnostic performance of SAMeTT 2 R 2 score., Methods: We prospectively included 212 consecutive patients with nonvalvular atrial fibrillation under treatment with acenocoumarol for at least 6 months that were attended in a cardiology outpatient clinic and were categorized as adherent to medication. We carried out a multivariate regression analysis to detect the independent predictive factors of good control. In all patients VKORC1 , CYP2C9 ⁎ 2 , CYP2C9 ⁎ 3 , and MIR133A2 genotyping was performed., Results: A total of 128 (60.4%) patients presented TTR <70% (average TTR = 63.2). We identified body mass index (OR 0.94, 95%CI 0.89-0.99, p=0.032) and regular vitamin K intake (OR 0.53, 95%CI 0.28-0.99, p= 0.046) as independent predictors of poor anticoagulation control. The discriminatory power of a clinical-genetic model derived from our cohort was significantly better compared to the SAMeTT 2 R 2 score (C-statistic 0.658 versus 0.524, p<0.001)., Conclusions: In our study the SAMeTT 2 R 2 score revealed a poor ability in the prediction of TTR. Besides SAMeTT 2 R 2 , body mass index and possibly vitamin K intake should be taken into account when deciding the optimal anticoagulation strategy. The information provided by the identified genotypes was marginal.

Aims: The efficacy and safety of oral anticoagulation (OAC) using the vitamin K antagonists (VKA) are closely associated with the quality of anticoagulation, reflected by time in therapeutic range (TTR). The SAMe-TT2R2 is a risk score developed to predict the quality of anticoagulation control among VKA users. To analyse the quality of anticoagulation and its clinical determinants based on different methods in a prospective cohort of atrial fibrillation patients on VKA treatment participating in the multicentre Spanish observational registry FANTASIIA., Methods and Results: Estimated TTR was calculated from Rosendaal, direct method, international normalized ratio variability, and NICE criteria. Time in therapeutic range values were compared for those patients with a SAMe-TT2R2 score 0-2 and >2. One thousand four hundred and seventy patients were analysed (56.4% male, mean age 74.1 ± 9.5 years). Mean TTR was 61.5 ± 25.1 with Rosendaal and 64.7 ± 24.2 with direct method. There was a high correlation between both methods (ρ = 0.805). The prevalence of poor anticoagulation control was 55%. Diabetes mellitus [odds ratio (OR) 1.38; P = 0.008], peripheral artery disease (PAD, OR 1.62; P = 0.048), and HAS-BLED (OR 1.13; P = 0.022) were independently associated with TTR < 70%. SAMe-TT2R2 score 0-2 had a higher mean TTR than patients with SAMe-TT2R2 >2 (P = 0.044), with a specificity of > 90% for predicting TTR < 70%. Patients with TTR < 70% had higher risk of events (21.7 vs. 16.8%; P = 0.021)., Conclusion: In a multicentre prospective registry, 55% of AF patients had poor anticoagulation control with diabetes mellitus, PAD, and HAS-BLED being independently associated with TTR < 70%. A high SAMe-TT2R2 scores had a high specificity for predicting a TTR < 70% as an indicator of poor quality anticoagulation.

Introduction and Objectives: Evidence for the efficacy and safety of oral anticoagulation with dicumarines in patients with atrial fibrillation (AF) on hemodialysis is controversial. The aim of our study is to evaluate the long-term prognostic implications of anticoagulation with dicumarines in a cohort of patients with non-valvular AF on a hemodialysis program due to end-stage renal disease., Methods: Retrospective, observational study with consecutive inclusion of 74 patients with AF on hemodialysis. The inclusion period was from January 2005 to October 2016. The primary variables were all-cause mortality, non-scheduled readmissions and bleeding during follow-up., Results: Mean age was 75±10 years; 66.2% were men and 43 patients (58.1%) received acenocoumarol. During a median follow-up of 2.40 years (IQR=0.88-4.15), acenocoumarol showed no survival benefit [HR=0.76, 95% CI (0.35-1.66), p=0.494]. However, anticoagulated patients were at increased risk of recurrent cardiovascular hospitalizations [IRR=3.94, 95% CI (1.06-14.69), p=0.041]. There was a trend towards an increase in repeated hospitalizations of ischemic cause in anticoagulated patients [IRR=5.80, 95% CI (0.86-39.0), p=0.071]. There was a statistical trend towards a higher risk of recurrent total bleeding in patients treated with acenocoumarol [IRR=4.43, 95% CI (0.94-20.81), p=0.059]., Conclusions: In this study, oral anticoagulation with acenocoumarol in patients with AF on hemodialysis did not increase survival. However, it was associated with an increased risk of hospitalizations of cardiovascular causes and a tendency to an increased risk of total bleeding., (Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Bleeding risk with vitamin K antagonists (VKAs) is closely related to the quality of anticoagulation in atrial fibrillation (AF) patients, reflected by time in therapeutic range (TTR). Here we compared the discrimination performance of different bleeding risk scores and investigated if adding TTR would improve their predictive value and clinical usefulness. We included 1361 AF patients stables on VKA for at least 6 months. Bleeding risk was assessed by the HAS-BLED, ATRIA, ORBIT and HEMORR 2 HAGES scores. Major bleeding events were recorded after a median of 6.5 years follow-up. In this period 250 patients suffered major bleeds. Comparison of receiver operating characteristic (ROC) curves demonstrated that HAS-BLED had the best discrimination performance, but adding the 'labile INR' criteria (i.e. TTR <65%) to ATRIA, ORBIT and HEMORR 2 HAGES increased their ability of discrimination and predictive value, with significant improvements in reclassification and discriminatory performance. Decision curve analyses (DCA) showed improvements of the clinical usefulness and a net benefit of the modified risk scores. In summary, in AF patients taking VKAs, the HAS-BLED score had the best predictive ability. Adding 'labile INR' to ATRIA, ORBIT and HEMORR 2 HAGES improved their predictive value for major bleeding leading to improved clinical usefulness compared to the original scores.

Background: Anti-phospholipid syndrome (APLS) is a condition characterized by the presence of raised plasma levels of anti-phospholipid antibodies associated with thrombo-embolic disease and/or poor obstetrical outcomes in women. The epidemiology of APLS is unknown in most sub-Saharan African countries due to limited access to diagnosis tools. We report the case of APLS in a 29-year-old obese woman that was preceded by pre-eclampsia and fetal death. The diagnosis of APLS was made during a thrombo-embolic episode 4 years after the poor obstetrical outcome. Her management was challenging, as she had three thrombo-embolic events within 18-months despite treatment with anti-coagulant (acenocoumarol)., Conclusion: This case highlights the need for screening for APLS after an episode of hypertensive disease in pregnancy or fetal death, and the challenges faced with the treatment, such as resistance to antivitamin K anti-coagulants and the desire for maternity.

Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion., Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis., Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

Background: The SAMe-TT2R2 (sex female, age, medical history, treatment, tobacco use, race) score was developed in patients with atrial fibrillation (AF) on warfarin. The present study aimed to 1) compare the anticoagulation quality and management of AF patients treated with warfarin with those on acenocoumarol and 2) optimize the SAMe-TT2R2 score to detect AF patients at high risk of unstable anticoagulation with acenocoumarol and warfarin., Methods: In a single-center retrospective study, 320 patients with AF, including 15 (5%) after valve replacement, aged 40-82 (median 70) years, including 203 (63%) receiving acenocoumarol and 117 (37%) treated with warfarin, were studied. The SAMe-TT2R2 score was modified based on the candidate factors retrieved from univariate regression and assessed using the receiver operating curves (ROC)., Results: A median SAMe-TT2R2 score was 2 (1-3). Proportions of patients with ≥ 2 points and 0-1 points in the SAMe-TT2R2 score who had the time in therapeutic range (TTR) ≤ 70% were similar (61 [67%] vs. 63 [56%], p = 0.11). A modified score, involving medical history (myocardial infarction [MI] and chronic obstructive pulmonary disease [COPD], 1 point), statin treatment (1 point) and tobacco use (2 points) had a higher area under the curve (AUC) in patients on acenocoumarol compared to SAMe- TT2R2 (0.66; 95% confidence interval 0.58-0.73 vs. 0.56; 0.48-0.64, p = 0.042); ≥ 1 point indicated TTR > 70% with a sensitivity and specificity of 61% and 63%, respectively., Conclusions: The SAMe-TT2R2 score is less effective in predicting unstable anticoagulation with acenocoumarol versus warfarin. Adding statin use and highlighting COPD and previous MI increases a predictive value of this score for acenocoumarol.

Hemorrhagic rupture is a very rare complication of a simple hepatic cyst. We report the first case of a totally extraperitoneal rupture of a recurrent cyst, occurred in a 73-year-old man who presented with acute right hypochondralgia. Computed tomography revealed the rupture of a large hemorrhagic cyst in the right liver lobe and the formation of a voluminous hematoma in the retroperitoneal space. Despite the absence of hemoperitoneum, the entity of the bleeding led us to perform an urgent and successful surgical intervention. A review of the literature was conducted. To date, 9 cases of hemorrhagic rupture of simple hepatic cyst have been described and our case is the first one characterized by extraperitoneal bleeding. Our clinical management was in accordance with the majority of the other Authors. Different surgical procedures have been proposed and the best approach has not been established yet. However, the laparotomic approach should be preferred for a better control of the bleeding. In conclusion, the hemorrhagic rupture of a liver cyst is a life-threatening complication and a prompt surgery is necessary to prevent the hypovolemic shock., Key Words: Extraperitoneal rupture, Hemorrhagic rupture, Simple hepatic cyst.

Aims: Randomized trials showed non-inferior or superior results of the non-vitamin-K-antagonist oral anticoagulants (NOACs) compared with warfarin. The aim of this study was to assess the effectiveness and safety of dabigatran (direct thrombin inhibitor) vs. acenocoumarol (vitamin K antagonist) in patients with atrial fibrillation (AF) in daily clinical practice., Methods and Results: In this observational study, we evaluated all consecutive patients who started anticoagulation because of AF in our outpatient clinic from 2010 to 2013. Data were collected from electronic patient charts. Primary outcomes were stroke or systemic embolism and major bleeding. Propensity score matching was applied to address the non-randomized design. In total, 920 consecutive AF patients were enrolled (442 dabigatran, 478 acenocoumarol), of which 2 × 383 were available for analysis after propensity score matching. Mean follow-up duration was 1.5 ± 0.56 year. The mean calculated stroke risk according to the CHA2DS2-VASc score was 3.5%/year in dabigatran vs. 3.7%/year acenocoumarol-treated patients. The actual incidence rate of stroke or systemic embolism was 0.8%/year [95% confidence interval (CI): 0.2-2.1] vs. 1.0%/year (95% CI: 0.4-2.1), respectively. Multivariable analysis confirmed this lower but non-significant risk in dabigatran vs. acenocoumarol after adjustment for the CHA2DS2-VASc score [hazard ratio (HR)dabigatran = 0.72, 95% CI: 0.20-2.63, P = 0.61]. According to the HAS-BLED score, the mean calculated bleeding risk was 1.7%/year in both groups. Actual incidence rate of major bleeding was 2.1%/year (95% CI: 1.0-3.8) in the dabigatran vs. 4.3%/year (95% CI: 2.9-6.2) in acenocoumarol. This over 50% reduction remained significant after adjustment for the HAS-BLED score (HRdabigatran = 0.45, 95% CI: 0.22-0.93, P = 0.031)., Conclusion: In 'real-world' patients with AF, dabigatran appears to be as effective, but significantly safer than acenocoumarol., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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., (© 2016 International Society on Thrombosis and Haemostasis.)

Objectives: After elective aortic valve replacement, patients are at risk of developing valve thrombosis and systemic arterial thromboembolism. Current guidelines recommend antithrombotic therapy with aspirin or vitamin K antagonists (VKAs) during the first 3 months after the procedure, but have level 2 or 3 evidence. As a consequence, the most appropriate antithrombotic therapy is still a matter of debate. This retrospective study analysed all thromboembolic and bleeding complications in patients with either antiplatelet or anticoagulation therapy 1 year after bioprosthetic aortic valve replacement., Methods: A total of 402 patients undergoing bioprosthetic aortic valve implantation at the VU University Medical Centre and subsequently treated at three regional hospitals were included. The individual duration of either VKAs (acenocoumarol) or aspirin was determined and related to thrombotic and bleeding events. Patients were followed and censored at 1 year postoperatively for survival, cerebral ischaemia, myocardial infarction, peripheral arterial embolism, and minor and major haemorrhages., Results: A total of 24 thromboembolic complications and 31 bleeding episodes occurred. Multivariable analyses revealed that acenocoumarol caused more bleeding episodes (risk ratio [RR]: 8.41, 95% CI: 3.58-19.79) and a similar amount of thromboembolic events (RR: 1.2, 95% CI: 0.47-3.02) compared with aspirin. Prior use of acenocoumarol was found to be a risk factor for thromboembolic events (RR: 3.1, 95% CI: 1.31-7.19). Gender, dyslipidaemia, prior percutaneous coronary intervention, prior use of acenocoumarol and concomitant coronary artery bypass grafting were found to be predictors for bleeding events., Conclusions: In patients 1 year following bioprosthetic aortic valve replacement, acenocoumarol therapy was associated with a significant increased risk of bleeding events and no reduction in thromboembolic events compared with antiplatelet therapy. These findings support the recommendations of aspirin over VKAs as postoperative thromboprophylaxis., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The anticoagulant therapy with acenocoumarol is generally associated with a high risk of bleeding and thromboembolic events., Purpose: We applied eight already existing acenocoumarol dosing algorithms to Bulgarian patients with low acenocoumarol dose requirements and investigated which of these algorithms would predict most precisely the dose anticoagulant., Materials and Methods: Two patients with Bulgarian origin were referred to the outpatient clinical laboratory of "St. Ekaterina" University Hospital for Cardiovascular Surgery and Cardiology, Sofia, Bulgaria. After obtaining written informed consent, both patients were genotyped for polymorphisms in genes for Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase (VKORC1), Apolipoprotein E (APOE), and Cytochrome P450 4F2 (CYP4F2)., Results: All applied acenocoumarol dosing algorithms predicted relatively similar doses of coumarin anticoagulant in both patients. However, van Schie et al.'s algorithm allowed more accurate calculation of the optimal dose in our patients with extremely low acenocoumarol requirements. Genotyping of selected polymorphic variants in CYP2C9 and VKORC1 showed that both patients were compound heterozygotes for CYP2C9 (CYP2C9*2/*3) and homozygotes for both variants in VKORC1 (VKORC1 1173 T/T, and VKORC1-1639 A/A). This combination of genotypes suggested high sensitivity to acenocoumarol leading to the low anticoagulant dose requirements (0.25 and 1 mg/day, respectively) needed to reach the target International Normalized Ratio of 2.5-3.5., Conclusions: The genotyping of polymorphic variants in VKORC1 and CYP2C9, together with clinical and demographic parameters, can serve for more precise definition of the individual starting and maintenance doses of coumarin derivatives in each patient.

Introduction and Aims: Anticoagulation control as assessed by time in therapeutic range (TTR) correlates positively with the safety and efficacy of thromboprophylaxis in atrial fibrillation. We set out to assess TTR in our unit and to investigate determinants of better control., Methods: This was a case series study of atrial fibrillation patients anticoagulated with warfarin or acenocoumarol at the Family Health Unit of Fânzeres. Sociodemographic and clinical data were collected and TTR was calculated by the Rosendaal method, based on international normalized ratio tests performed in external laboratories in the preceding six months. SPSS 21.0 was used for the statistical analysis, with descriptive statistics, Spearman's correlation, and the Mann-Whitney U and Kruskal-Wallis tests., Results: Of the 106 eligible patients, 70% participated in the study. Median TTR was 65.3% (P25=48.3%, P75=86.8%). We found a positive association between this variable and duration of atrial fibrillation (ρ=0.477, p<0.001, r(2)=0.116) and with duration of anticoagulation (ρ=0.5, p<0.001, r(2)=0.087). No association was found with age, gender, educational level or existence of a caregiver (p>0.05)., Conclusions: Median TTR in our unit is similar to that in southern European countries and close to the good control threshold (70%) proposed by the European Society of Cardiology. The duration of atrial fibrillation and of anticoagulation explains only a small part of the measure's variability. Other determinants of anticoagulation control must be investigated in future studies and comparative studies should be carried out in family health units monitoring anticoagulation on the premises., (Copyright © 2014 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Background: Acenocoumarol is a vitamin K antagonist used in some European countries. As warfarin, this drug is characterized by a narrow therapeutic index and a large interindividual variability., Aim: The objective of this study was to assess the involvement of ABCB1 polymorphisms on acenocoumarol treatment., Materials & Methods: An observational cohort study was conducted to assess whether there is an association between the presence of the allelic variants of the ABCB1 gene coding for P-glycoprotein and acenocoumarol stabilization and daily doses during the first 35 days of treatment., Results: One hundred and fifteen patients met the inclusion criteria. The results of the clinical study showed that carriers of ABCB1 c.3435TT were more rapidly stabilized than wild-type patients (HR: 2.97, 95% CI: 1.23-7.18; p = 0.02). The same tendency was observed for the ABCB1 c.2677GT and 2677TT genotypes compared with ABCB1 c.2677GG. The ABCB1 c.2677TT genotype was also associated with a significant increase in doses of acenocoumarol (p = 0.03), the same tendency was observed with the ABCB1 c.3435TT genotype compared with the wild-type patients., Conclusion: These data suggest that ABCB1 polymorphisms could be involved in the response to acenocoumarol treatment.

Aims: Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs., Methods: The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins)., Results: Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity-concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity-concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001)., Conclusions: Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention., (© 2014 The British Pharmacological Society.)

Objectives: To analyse the relationship between an automated thrombin generation test, the endogenous thrombin potential (ETP), and other hypercoagulability markers, with vascular involvement in patients with Behçet's disease (BD). Patients and methods. We analysed 56 BD patients (30 men; mean age, 34.4 ± 14.3 years) without any known thrombophilic factor, of which 17 had previously suffered from thrombosis (deep venous thrombosis in 14 and ischaemic stroke in 3), and 56 controls matched for age and sex. Additionally, we also evaluated 20 plasma samples with an international normalised ratio (INR) between 1.5 and 5.0 obtained from patients with atrial fibrillation but without a history of embolic events that were under treatment with acenocumarol. Thrombin generation was measured as ETP with a chromogenic assay in an automated analyser. Factor VIII, von Willebrand factor antigen, prothrombin fragment 1.2, D-dimer and plasmin-antiplasmin complexes were also measured., Results: BD patients showed higher ETP values than controls (471.3± 49.3 vs. 427.5± 31.3 mA; p<0.001). Additionally, BD patients with a history of thrombosis had higher ETP values than patients without thrombosis (496.6± 36.5 vs. 460.7± 50.5 mA; p<0.01). Factor VIII and von Willebrand factor antigen were also elevated in BD patients, but only von Willebrand factor antigen showed statistically significant differences between BD patients with and without thrombosis. Acenocumarol treatment reduced thrombin generation in BD patients in parallel to INR levels, reaching values similar to those of patients with atrial fibrillation and similar INR., Conclusions: BD is associated with thrombosis, and increased thrombin generation (measured as ETP) is a promising marker of hypercoagulability.

Oral anticoagulants of the coumarin type have an inconveniently narrow therapeutic window, making their use difficult. In Mexico, genetic variables that participate in the heterogeneity of the therapeutic response remain poorly investigated. With the focus on warfarin, extensive pharmacogenomic studies have been performed, including those on the CYP450 family and APOE. The objective of this study was to determine the contribution of CYP2C9, CYP2C19, and APOE polymorphisms to the variations in response to the doses of acenocoumarol, which is the main anticoagulant prescribed to the Mexican population. The polymerase chain reaction-restriction fragment length polymorphism method was applied to identify 2 and 3 of CYP2C9, 2 of CYP2C19, and APOE variants. The genetic distribution of every polymorphism tested showed high variability when compared with other populations worldwide. Our results showed statistical differences only in the CYP2C19 gene between the 1 1 and 1 2 groups, with effective acenocoumarol doses of 2.56 ± 1.34 mg/day vs 1.35 ± 0.84 mg/day (P = 0.005), respectively. Multiple regression analysis, including patient age and both the CYP2C9 and CYP2C19 genes, showed that these variables explained more than 20% of the dose variations. This is the first report in Mexico searching for the relationship between CYP450 and APOE polymorphisms and the dose requirements of acenocoumarol. Our results suggest that, in the Mexican population, CYP2C19 is more involved in acenocoumarol metabolism than CYP2C9 and APOE. Besides considering the age factor, pharmacogenetic testing for CYP2C19 2 before initiating acenocoumarol treatment could lead to a safer anticoagulation therapy in Mexican patients.

Although traditionally observed in patients with end-stage renal disease and secondary hyperparathyroidism, calciphylaxis has been reported in patients with normal renal and parathyroid function. There is no evidence-based therapy available. The use of sodium thiosulfate (STS) has been increasingly described. Herein we describe two patients who responded well to this treatment.

Lenalidomide has significant antimyeloma activity but it is associated with a significant risk of venous thromboembolism (VTE). In this study, we assessed clinical and genetic risk factors that may predispose for VTE in myeloma patients who were treated with lenalidomide-based regimens. We analyzed common clinical and selected genetic factors in 200 consecutive, unselected myeloma patients who were treated with lenalidomide-based regimens in a single institution. Twelve patients (6%) developed a VTE (nine deep venous thrombosis and three pulmonary embolism). All VTEs occurred in patients who were receiving aspirin prophylaxis; no patient who received LMWH or acenocoumarol had a VTE. The frequency of VTEs was 9.4% in previously untreated and 4.5% in previously treated patients. VTEs were more frequent in patients >65 years (8.1% vs. 1.6%) especially among patients receiving aspirin as prophylaxis (10.4% vs. 1.8% for patients ≤65 years). In patients who received prophylaxis with low dose aspirin a single-nucleotide polymorphism in NFκB1 (rs3774968) gene was associated with increased risk of VTE (OR 3.76, 95%CI 1-16, P = 0.051). None of the patients who developed VTEs had common genetic variations that are associated with increased risk of VTEs in the general population, such as FVLeiden and FIIG20210A. Our data indicated that LMWH or vitamin K antagonists (with a target INR 2-3) effectively reduce the risk of VTEs. In patients who received prophylaxis with aspirin genetic variants of genes that are involved directly or indirectly in inflammatory response may be associated with increased risk of VTE., (Copyright © 2013 Wiley Periodicals, Inc.)

We present a case of a 67-year-old male with pulmonary embolism. Transesophageal echocardiography (TEE) showed the presence of a mobile thrombus straddling the patent foramen ovale (PFO) and prolapsing into both atria. Treatment with heparin was started. Five days after admission, repeat TEE revealed a reduction in thrombus dimensions, so anticoagulation therapy was continued. Eleven days after admission, TEE showed complete disappearance of the thrombus.

Pulmonary arterial hypertension is a rare and devastating disease characterized by vascular proliferation and remodeling. Epoprostenol, the drug counterpart of the eicosanoid prostacyclin, produced by the vascular endothelial cells, is the drug of choice for this disease. Its capacity to act rapidly and to significantly improve survival prospects in severe pulmonary hypertension patients has been supported by a wealth of evidence. Intravenous epoprostenol was believed to require therapy of indefinite duration. Since 2001, oral drugs have been approved for specific treatment. The availability of newer and less invasive drug therapies for pulmonary arterial hypertension led physicians to withdraw epoprostenol in carefully selected patients. We report a case of successful intravenous epoprostenol interruption in a patient with idiopathic disease. A literature review on epoprostenol withdrawal in pulmonary hypertension in adult patients is also provided., (© 2013 Daedalus Enterprises.)

Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures., Objectives: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol., Patients/methods: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability., Results: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures., Conclusions: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol., (© 2012 International Society on Thrombosis and Haemostasis.)

Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.

Acenocoumarol is a vitamin K antagonist that is used for the treatment of acquired and congenital, both arterial and venous, thrombotic diseases. Its use is complicated by the narrow therapeutic range. Bleeding following oral anticoagulation, despite rare, remains the major complication. Most cases of hemorrhagic episodes usually require short hospitalization and transfusion, while surgical drainage of the hematoma is not recommended. However, in cases that conservative treatment isn't successful, surgical intervention remains an option. We present a case of severe spontaneous bleeding of the rectus abdominis muscle which was successfully managed surgically.

Objectives: To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction., Methods: Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1 -1639 G>A, CYP4F2 1347 G>A, CYP2C9*2,*3 and GGCX 12970 C>G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated., Results: The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4% (p-value <0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under-estimation in comparison to clinical data. The VKORC1-1639 G>A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model., Conclusions: We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm which might become a baseline for personalised medicine approach for treatment of patients in future.