Pharmacoeconomics of anticoagulation therapy for stroke prevention in atrial fibrillation: a review

INTRODUCTION: Atrial fibrillation (AF) increases the risk of ischemic stroke 5-fold and may not only be responsible for as many as 15% of all strokes that occur but also for larger and more disabling strokes than those attributable to other causes which increase the associated costs of care. Anticoagulation with warfarin in the target INR of 2.5 is a major clinical challenge in real-life practice, given that the complex relationship between warfarin dosage and response is readily altered by a variety of factors such as concurrent medications, illnesses, genetic influences, and dietary/lifestyle changes. Consequently, INR values are out of the target range approximately half of the time in real-life studies compared to clinical trial setting. Current anticoagulation therapies are less likely to be cost-effective in routine clinical practice and need improvement. The aim of this review is to discuss the pharmacoeconomic consequences of this management strategy by analysing the optimal treatment option within specific age and risk groups, confirming current guidelines for a health economic perspective and considering the economic impact on health care policy. METHODS: An electronic search of the Medline/PubMed database from 1966 to 2005 was performed to identify articles dealing with all pharmacoeconomic aspects of stroke prevention in atrial fibrillation. The following search terms were used: 'atrial fibrillation', 'stroke', 'cost', 'warfarin'. RESULTS: Treatment with warfarin is cost-effective (versus aspirin or no therapy) in patients with AF at moderate-to-high risk of stroke. The cost-effectiveness of anticoagulation therapy is driven by the achieved risk reduction rather than the potential benefits estimated from clinical trials. Failure to maintain optimal anticoagulation places patients at risk of complications, the management of which is a significant cost driver. CONCLUSION: Improvement could be achieved by optimising physicians and patient's knowledge driven through prevention campaigns by health care policy.     

Finding the optimal dose of vitamin K1 to treat vitamin K deficiency and to avoid anaphylactoid reactions

Vitamin K1 injection induces severe dose‐related anaphylactoid reactions and overdose for the treatment of vitamin K deficiency. We aimed to find an optimal and small dose of vitamin K1 injection to treat vitamin K deficiency and avoid anaphylactoid reactions in animal. Rats were administered a vitamin K‐deficient diet and gentamicin to establish vitamin K deficiency model. Behaviour tests were performed in beagle dogs to observe anaphylactoid reactions. The results showed an increased protein induced by vitamin K absence or antagonist II (PIVKA‐II) levels, a prolonging of prothrombin time (PT) and activated partial thromboplastin time (APTT) and a decrease in vitamin K‐dependent coagulation factor (F) II, VII, IX and X activities in the model group. In vitamin K1 0.01 mg/kg group, the liver vitamin K1 levels increased fivefold and the liver vitamin K2 levels increased to the normal amount. Coagulation markers PT, APTT, FVII and FIX activities returned to normal. Both in the 0.1 and 1.0 mg/kg vitamin K1 groups, coagulation functions completely returned to normal. Moreover, the amount of liver vitamin K1 was 40 (0.1 mg/kg) or 100 (1.0 mg/kg) times as in normal. Vitamin K2 was about 4 (0.1 mg/kg) or 5 (1.0 mg/kg) times as the normal amount. There was no obvious anaphylactoid symptom in dogs with the dose of 0.03 mg/kg, which is equivalent to the dose of 0.01 mg/kg in rats. These results demonstrated that a small dose of vitamin K1 is effective to improve vitamin K deficiency and to prevent anaphylactoid reactions, simultaneously.     

Plasma Prothrombin during Treatment with Dicumarol

Ganrot, P. O. & Niléhn, J.-E. Plasma Prothrombin during Treatment with Dicumarol. II. Demonstration of an abnormal prothrombin fraction. Scand. J. clin. Lab. Invest. 22, 23-28, 1968.

Immunochemical analysis of plasma from patients treated with Dicumarol revealed the co-occurrence of two fractions of prothrombin. They could be separated completely by agarose gel electrophoresis. One of the fractions behaved like prothrombin of plasma from subjects not treated with Dicumarol and was therefore called the ‘normal’ prothrombin. The other fraction did not form a complex with calcium ions, it was not activated on recalcification of citrated plasma, and it could not be absorbed with barium sulphate precipitate. An immunochemical method was devised for quantitative determination of the ‘normal’ prothrombin fraction. In individual plasma samples from 52 patients, some receiving treatment with Dicumarol, a very close correlation (r=0.946) was found between the concentration of ‘normal’ prothrombin and the prothrombin-proconvertin activity.     

ROTEM monitoring of activated and non-activated prothrombin complex concentrate correction of dilutional coagulopathy

Objectives Prothrombin complex concentrates have been used to correct dilutional coagulopathy, but many preparations contain anticoagulants, such as heparin, to counteract their prothrombotic effects. These anticoagulants can interfere with haemostatic assays. The aim of this study was to monitor two different prothrombin complex concentrates for the treatment of albumin dilution in vitro, using rotational thromboelastometry with or without the heparin-antagonising agent protamine. Methods Citrated blood from 10 healthy volunteers was, in vitro, diluted 1:1 with 5% albumin and then corrected with a four-factor prothrombin complex concentrate with heparin anticoagulant (Confidex®) corresponding to a clinical dose of 43?IU/kg. Blood samples were tested with or without protamine. An activated prothrombin complex concentrate (APCC) (FEIBA®) without heparin in doses of 50?IU/kg and 100?IU/kg was also tested. Thromboelastometry was performed after recalcification. Results Albumin dilution significantly affected all thromboelastometry parameters. The four-factor PCC had an additional anticoagulant effect when added to the albumin-diluted blood; it was partially corrected by protamine for all parameters except maximum clot firmness. The APCC significantly improved all parameters, with over-correction of clotting time but only partial correction of maximum clot firmness. Conclusions The anticoagulant content of many prothrombin complex concentrates needs to be considered when performing in vitro testing. A heparin-free APCC better corrected an in vitro albumin-induced dilutional coagulopathy than a four-factor PCC, despite of blocking heparin with protamine.     

Emergency reversal of pentasaccharide anticoagulants: a systematic review of the literature

Objectives: To conduct a systematic review of the literature to answer the question: Has administration of recombinant activated factor VII (rFVIIa) or prothombin complex concentrate (PCC) or activated PCC (aPCC) been demonstrated to be effective in reversing pendasaccharide anticoagulants (PSAs)? Background: Fondaparinux and idraparinux are ultra‐short, synthetic PSAs. Typical anticoagulation reversal with either vitamin K and fresh frozen plasma or protamine sulphate does not reverse PSAs. Mechanistically, it is plausible that rFVIIa, PCC and aPCC may be effective reversal agents for PSAs. However, the available data are limited. Materials/Methods: We conducted a systematic review of MEDLINE, EMBASE, CINAHL and the Cochrane Library without date or language limitations designed to answer the question: Has administration of rFVIIa, PCC or aPCC been demonstrated to be effective in reversing PSAs? The quality of the included studies was assessed based on standard methodologies. Relevant information was synthesised and reported. Results: After an initial literature search, 197 abstracts were identified, of which 14 articles were reviewed in their entirety. Ultimately, five studies were identified that met inclusion and exclusion criteria. Although the literature is limited, the best available data support the use of rFVIIa for serious bleeding in patients anticoagulated with PSAs. Conclusions: Limited data support the use of rFVIIa as a reversal agent for serious bleeding in patients who are anticoagulated with PSAs. The optimal dose, role for concomitant use of platelets or antifibrinolytic agents and exact indications for reversal remain to be determined. Such investigations are urgently needed as use of PSAs increases.     

Sustained intake of paracetamol (acetaminophen) during oral anticoagulant therapy with coumarins does not cause clinically important INR changes: a randomized double-blind clinical trial

Summary.  Paracetamol (acetaminophen) is routinely advised when non-steroidal anti-inflammatory drugs (NSAID) are necessary during oral anticoagulant treatment (OAT) because it has no relevant effect on the primary hemostasis. However, in a recent case-control study a dose-related effect was observed of paracetamol intake on the International Normalized Ratio (INR) values making its use controversial during OAT. Our objectives were to determine the effect of paracetamol on the INR values during OAT independent of underlying illness. A double-blind randomized controlled trial in which 31 out-patients on coumarin oral anticoagulant therapy with phenprocoumon, aged 18–70 years, with a planned treatment duration of more than 12 weeks, and an INR target range of 2.5–3.5, were included. Patients were randomized for placebo (10 patients), paracetamol 1500 mg daily (11 patients) or paracetamol 3000 mg daily (10 patients) for 14 days during the stable phase of coumarin OAT and INR values at day 1, 8, 15, 22 and 29 were measured. At day 8 a mean rise of 0.46 INR was seen in both paracetamol groups compared to placebo. At day 15 there was no difference between placebo and paracetamol 1500 mg daily, and a small mean rise of 0.22 INR in the paracetamol 3000 mg daily group. The sustained use of paracetamol (acetaminophen) during oral anticoagulant therapy in itself does not provoke clinically relevant INR changes. Any important INR rise will predominantly be the result of the illness necessitating the intake of this medication. A difference has to be made between those patients taking paracetamol (acetaminophen) for pain relief or as an antipyretic during infectious diseases.     

Vitamin K Antagonist Treatment in Patients With Atrial Fibrillation and Time in Therapeutic Range in Four European Countries

Purpose

Patients with atrial fibrillation are at increased risk for stroke and thus require anticoagulant prophylaxis with vitamin K antagonists. However, many such patients fail to achieve target coagulation status. The objective of this study was to evaluate time in the therapeutic range and its relationship to clinical outcomes in patients with nonvalvular atrial fibrillation prescribed a vitamin K antagonist in everyday clinical practice in 4 European countries (France, Germany, Italy and the United Kingdom).

Methods

Data were extracted from the European electronic primary care database, the Longitudinal Patient Database. Included in the analysis were 6250 adult patients for whom data on monitoring of coagulation time and international normalized ratio were available. The time within the therapeutic range was estimated by using the Rosendaal method. Patients spending >70% of time within the therapeutic range were considered to have well-controlled treatment. Data on stroke and bleeding events occurring during the study period were taken from patient records. Stroke risk was calculated by using the CHA₂DS₂-VASc score (i.e. 2 points for a history of stroke or TIA and age >75years, and 1 point for age between 65 and 74 years, hypertension, diabetes mellitus, a recent cardiac failure, vascular disease and female sex).

Findings

The proportion of patients with poorly controlled treatment varied from 34.6% in the United Kingdom to 55.8% in Germany. The incidence of stroke was 0.5/100 person-years in well-controlled patients, compared with 1.0/100 in poorly controlled patients. After adjustment for stroke risk factors, the odds ratio was 1.38 (95% CI, 0.93–2.06; P = 0.110). The incidence of hemorrhage was 1.1 and 1.3 events/100 person-years, respectively (odds ratio, 0.91 [95% CI, 0.72–1.16]).

Implications

Many patients receiving prophylaxis with vitamin K antagonists in everyday community care have poorly controlled anticoagulation treatment with vitamin K antagonists. Their international normalized ratio is frequently outside the therapeutic range, and they are thus exposed to an unnecessary risk of stroke or bleeding complications.     

Prothrombin complex concentrate (Beriplex® P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial

Summary.  Background:  Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). Objectives.  To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex^® P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S. Patients and methods:  Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg⁻¹ PCC doses were infused based on initial INR. Study endpoints included INR normalization (≤1.3) by 30 min after PCC infusion and hemostatic efficacy. Results:  Forty-three patients, 26 requiring interventional procedures and 17 experiencing acute bleeding, received PCC infusions at a median rate of 7.5 mL min⁻¹ (188 IU min⁻¹). At 30 min thereafter, INR declined to ≤1.3 in 93% of patients. At all postinfusion time points through 48 h, median INR remained between 1.2 and 1.3. Clinical hemostatic efficacy was classified as very good or satisfactory in 42 patients (98%). Prompt and sustained increases in circulating coagulation factors and anticoagulant proteins were observed. One fatal suspected pulmonary embolism in a patient with metastatic cancer was judged to be possibly PCC-related. Conclusions:  PCC treatment serves as an effective rapid hemorrhage control resource in the emergency anticoagulant reversal setting. More widespread availability of PCC is warranted to ensure its benefits in appropriate patients.     

Evaluation of vitamin K deficiency in children with acute and intractable diarrhea

The purposes of this study were to determine the frequency of vitamin K deficiency and to assess its effects on bleeding in patients with acute and intractable diarrhea. A total of 90 children with diarrhea and 30 healthy children (group C) were included in this study. Patients were divided into 2 groups, according to the duration of diarrhea. Complete blood count; prothrombin time (PT); activated prothrombin time (APTT); Factors II, VII, IX, and X; and protein C levels were studied in all patients. A total of 3 mg of vitamin K was administrated to patients with prolonged PT and/or APTT. Coagulation parameters were restudied 8 to 12 h after vitamin K was administered. Mean age, sex, weight, and breastfeeding percentage, as well as history of fever and vitamin K administration at birth, were similar in the 2 groups. The duration of antibiotic administration in group B (intractable diarrhea) was significantly longer than that in group A (acute diarrhea). Gastrointestinal (GI) bleeding was observed in 3 (4.9%) infants in group A and 6 (20.7%) in group B (P< .05). The duration of diarrhea was significantly longer in infants with GI bleeding. Intracranial bleeding occurred in 1 infant with intractable diarrhea. Prolonged PT levels were noted in groups A and B. Significant improvement in PT and APTT and an increase in coagulation factors were observed after vitamin K had been administered. Investigators in this study conclude that coagulation parameters can be improved by the administration of vitamin K to children with deranged PT and APTT and diarrheal illness.     

Intensive blood and plasma exchange for treatment of coagulopathy in meningococcemia

Eight pediatric patients with fulminant meningococcemia, purpura, and disseminated intravascular coagulation who by multiple prognostic scoring systems were anticipated to have a poor outcome underwent intensive plasma exchange (IPE) or whole blood exchange (WBE) in addition to standard medical therapy. IPE/WBE was initiated shortly after admission with a mixture of both fresh frozen plasma and cryoprecipitate as the replacement solution. All IPE procedures were performed using a continuous flow system and a red cell prime. The mean fibrinogen level increased from 62 to 192 mg/dl, the prothrombin time (PT) decreased from a mean of 32.4 seconds to 15.1 seconds, and the mean activated partial thromboplastin time (APTT) decreased from 89.5 seconds to 40.1 seconds following completion of the initial IPE/WBE. There was a corresponding improvement in all coagulation factor levels but only slight improvement in antithrombin III (ATIII) and protein C levels. Seven of eight patients survived (87.5%) their initial presentation with the sole early death attributed to meningitis with cerebral edema. Mean fluid balance after the procedure was + 10.8 ± 5.87 cc/kg. There were no significant bleeding or cardiovascular complications during the procedure. There was no clinical or radiographic evidence of fluid overload after the procedure. This experience demonstrates that IPE/WBE may be conducted safely in critically ill, unstable pediatric patients and is effective in rapidly improving coagulopathy without fluid overload.     

Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Summary. Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta‐analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I² 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy‐related VTE, but the optimal dosing regimens remain uncertain.     

Associations between socioeconomic status,atrial fibrillation,and outcomes: a systematic review

ABSTRACT

Background: Atrial fibrillation (AF) is a growing epidemic and evidence of a relationship to socioeconomic status (SES) is inconsistent. We aimed to summarize the literature about SES and AF and defined two objectives: (1) To examine the association between SES and the risk of AF; (2) To examine the association between SES and AF-related outcomes in an AF-population.

Methods: We performed a separate search for each objective in Ovid-MEDLINE and Ovid-Embase. For objective 1, the population included was healthy participants and outcome of interest was AF. For objective 2, the population included were patients with AF and outcome of interest was mortality, treatment, ablation for AF, knowledge about AF, and morbidity.

Results: For objective 1, 12 studies were included. No consistent pattern for an association between SES and the risk of AF was discovered. For objective 2, 39 studies comprising 42 outcomes were included. The majority of studies showed an association between low SES and increased mortality and morbidity.

Conclusion: Low SES was associated with poorer outcomes when AF was present. These findings may imply that health-care professionals and policy interventions should focus on the promotion of AF-education and management among patients with AF and low SES.     

晚发型维生素K缺乏性出血症的临床分析及预防对策

目的 分析晚发型维生素K缺乏性出血症(VKDB)的临床特征,并总结其预防对策.方法 将2019年9月至2021年8月本院收治的100例晚发型VKDB患儿设为观察组,选取同期于本院出生的100名健康婴儿为对照组,两组均展开凝血功能指标(PT、APTT、TT、CT)、维生素K缺乏诱导蛋白-Ⅱ(PIVKA-Ⅱ)、维生素K1(...     

妊娠晚期维生素K1营养状况对凝血功能检测结果的影响

目的 探讨妊娠晚期维生素K1(VK1)营养状况对凝血功能检测结果的影响.方法 选择2019年4月至2019年10月来我院分娩的823例正常孕妇作为研究对象,按照血清VK1水平将其分为正常组(440例)、缺乏组(15例)和过量组(368例);按照年龄将其分为适龄组(681例)和高龄组(142例).比较不同年龄组孕妇的VK...     

Treatment of pulmonary brucellosis: a systematic review

Introduction: Pulmonary involvement is a rare, focal complication of human brucellosis. The aim of this review is to describe clinical and radiologic features, treatment administered and clinical course of these patients.

Areas covered: We conducted a systematic search of scientific reports of brucellosis with pulmonary involvement published from January 1985 to July 2016. Four main patterns of disease were observed: pneumonia, pleural effusion, nodules and interstitial pattern. Cough and fever were the most common symptoms. Brucella spp. culture was obtained from blood (50%) or pleural fluid. Treatment is based on the same antibiotics and combinations of antibiotics as for patients with acute no complicated brucellosis. The most frequent antimicrobial combination was doxycycline and rifampin for six weeks. The clinical course was favorable in most reports, and mortality was remarkably low (<1%).

Expert commentary: Non-specific clinical and radiological manifestations were the main reason for the delay in proper treatment. Difficulty in distinguishing Brucellosis from other pulmonary infections, such as tuberculosis, sometimes posed an added diagnostic challenge.     

Treatment of femoroacetabular impingement: a systematic review

The purpose of this review is to determine if there is a difference in outcomes after: (1) nonsurgical vs surgical treatment of FAI; (2a) surgical dislocation with greater trochanteric osteotomy, (2b) anterior mini-open, (2c) arthroscopic plus mini-open, and (2d) arthroscopic surgery for FAI; (3) difference in complication and re-operation rates; and (4a) labral refixation and (4b) labral debridement for labral injuries. A systematic review of multiple databases was performed after PROSPERO registration and using PRISMA guidelines. Level I-IV evidence clinical studies with minimum 2-year follow-up were included. Data were compared using 2-sample and 2-proportion Z-test calculators. Study methodological quality was analyzed using Modified Coleman Methodology Score (MCMS). Recommendations were made using SORT (Strength Of Recommendation Taxonomy). Twenty-nine studies were included (2369 subjects; 2507 hips). MCMS was poor. Mean subject age was 34.4+/−8.4 years and mean follow-up was 3.1+/−0.9 years. Statistically significant differences were observed following both nonsurgical and surgical treatment, with greater (P < 0.05) improvements following surgery (SORT B), without consistent significant differences observed between different surgical techniques (SORT C). There was a greater (P < 0.05) reoperation and complication rate following surgical dislocation vs mini-open and arthroscopic techniques (SORT A). Clinical outcomes were significantly better (P < 0.05) following labral refixation vs debridement (SORT B). Outcomes of operative treatment of femoroacetabular impingement are significantly better than nonsurgical management. Surgical treatment significantly improves outcomes, with no consistent significant differences exhibited between open and arthroscopic techniques. Open surgical dislocation has significantly greater reoperation and complication rates vs mini-open and arthroscopic techniques. Outcomes of labral refixation are significantly better than debridement in patients with labral injuries.     

Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma‐derived or recombinant factor VIII concentrates: a systematic review

Summary. Background: Different rates of inhibitor development after either plasma‐derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta‐regression and analysis‐of‐variance were used to investigate the effect of covariates (testing frequency, follow‐up duration and intensity of treatment). Results: Two thousand and ninety‐four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4–19.4) for pdFVIII and 27.4% (23.6–31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2–13.7) for pdFVIII and 17.4% (14.2–21.2) for rFVIII. In the multi‐way anova study design, study period, testing frequency and median follow‐up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.     

围术期桥抗凝治疗的研究现状

许多因静脉血栓栓塞症（VTE）、机械性心脏瓣膜或房颤而长期给予华法林抗凝治疗的患者在行重大外科手术或有创性操作时需停用华法林。在围术期以治疗性剂量普通肝素或低分子肝素暂时替代维生素K拮抗剂（VKA）治疗的方法称为桥抗凝治疗。桥抗凝治疗的目的是减少患者暂时停用VKA治疗时发生血栓栓塞事件的风险,但也可能增加患者发生严重出血并发症的风险。此文对围术期桥抗凝治疗的研究现状给予综述。