Oral Anticoagulant Therapy—When Art Meets Science

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.

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Morbidly Obese Patient on Rivaroxaban Presents With Recurrent Upper Extremity Deep Vein Thrombosis: A Case Report

Journal of Pharmacy Practice ◽

10.1177/0897190019851358 ◽

2019 ◽

Vol 33 (5) ◽

pp. 712-719 ◽

Cited By ~ 2

Author(s):

Sin-Ling T. Jennings ◽

Khanh N. P. Manh ◽

Jusilda Bita

Keyword(s):

Deep Vein Thrombosis ◽

Obese Patient ◽

Upper Extremity ◽

Oral Anticoagulants ◽

Morbidly Obese ◽

Vein Thrombosis ◽

Morbidly Obese Patient ◽

The Right ◽

Direct Acting ◽

Deep Vein

A morbidly obese patient with history of deep vein thrombosis and pulmonary embolism was diagnosed with an acute left upper extremity deep vein thrombosis and started on rivaroxaban. Three months later, the patient returned with swelling in the right arm and was found to have a right brachial thrombosis. Anticoagulant therapy was switched to a low-molecular-weight heparin, and patient was discharged on enoxaparin along with an order to follow-up with a hematologist. Subanalyses from randomized controlled trials, pharmacokinetic/pharmacodynamic, and real-world studies suggest that rivaroxaban may be effective and safe in morbidly obese patients for primary and secondary prevention of venous thromboembolism. However, the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis does not recommend the use of direct-acting oral anticoagulants in this population. If used, drug levels should be monitored to guide the therapy. Due to the disparity in data to show efficacy and safety of rivaroxaban in morbidly obese subjects, the interpatient variability of rivaroxaban’s effects in subjects, and the lack of defined therapeutic range for rivaroxaban drug concentration, rivaroxaban should be used cautiously in this population.

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Prevention of the post thrombotic syndrome with anticoagulation: a narrative review

Thrombosis and Haemostasis ◽

10.1055/a-1711-1263 ◽

2021 ◽

Author(s):

Ilia Makedonov ◽

Susan R Kahn ◽

Jameel Abdulrehman ◽

Sam Schulman ◽

Aurélien Delluc ◽

...

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Economic Consequences ◽

Compression Stockings ◽

Vein Thrombosis ◽

Post Thrombotic Syndrome ◽

Preventative Measures ◽

Catheter Directed Thrombolysis ◽

Deep Vein

The post thrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of VTE and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings (ECS) and pharmacomechanical catheter directed thrombolysis (PCDT). However, the efficacy of these treatments has been questioned by large RCTs. So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists (VKA), low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs)). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT.

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Direct oral anticoagulants and venous thromboembolism

European Respiratory Review ◽

10.1183/16000617.0025-2016 ◽

2016 ◽

Vol 25 (141) ◽

pp. 295-302 ◽

Cited By ~ 10

Author(s):

Massimo Franchini ◽

Pier Mannuccio Mannucci

Keyword(s):

Venous Thromboembolism ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Thrombin Inhibitors ◽

Vein Thrombosis ◽

Direct Anticoagulants ◽

Deep Vein

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a major clinical concern associated with significant morbidity and mortality. The cornerstone of management of VTE is anticoagulation, and traditional anticoagulants include parenteral heparins and oral vitamin K antagonists. Recently, new oral anticoagulant drugs have been developed and licensed, including direct factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g. dabigatran etexilate). This narrative review focusses on the characteristics of these direct anticoagulants and the main results of published clinical studies on their use in the prevention and treatment of VTE.

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Duration of Oral Anticoagulant Therapy after Proximal Deep Vein Thrombosis: a Decision Analysis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642432 ◽

1994 ◽

Vol 71 (03) ◽

pp. 286-291 ◽

Cited By ~ 24

Author(s):

François P Sarasin ◽

Henri Bounameaux

Keyword(s):

Deep Vein Thrombosis ◽

Decision Analysis ◽

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Oral Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Lower Limbs ◽

Vein Thrombosis ◽

Deep Vein

SummaryThe optimal duration of oral anticoagulant therapy following proximal deep vein thrombosis (DVT) in the lower limbs remains controversial. To compare the risk benefit tradeoffs for different treatment durations (6 to 24 weeks) we constructed a Markov-based decision analysis model which explicitly balances the time-dependent declining risk of recurrent thrombosis and pulmonary embolism against the risk of major hemorrhagic complications. Specifically, we determined the threshold below which the risk of recurrent DVT exceeds the risk of major hemorrhage if anticoagulant therapy is discontinued, and above which the benefits provided by oral anticoagulants are outweighed by their risk.Our model shows that for patients with a low hemorrhagic risk (0.5%/month), the benefit yielded by oral anticoagulants breaks off beyond the 4th month of therapy, while patients with moderate (1%/month) to high (2%/month) bleeding risk will no longer benefit from the therapy after 3 or 2.5 months, respectively.In conclusion, our model supports the validity of the usually recommended duration of 3 months of oral anticoagulation after proximal vein thrombosis in the lower limbs, but suggests that this duration should be modulated between 2.5 and 4 months depending upon individual bleeding risk. Since clinical trials can hardly handle the complexity of the addressed issue, such a model may prove very helpful in daily clinical practice.

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Pulmonary Embolism and Coexisting Deep Vein Thrombosis: A Detrimental Association?

Journal of Clinical Medicine ◽

10.3390/jcm8060899 ◽

2019 ◽

Vol 8 (6) ◽

pp. 899 ◽

Cited By ~ 1

Author(s):

Elena-Mihaela Cordeanu ◽

Hélène Lambach ◽

Marie Heitz ◽

Julie Di Cesare ◽

Corina Mirea ◽

...

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Prognostic Significance ◽

Vein Thrombosis ◽

All Cause Mortality ◽

Deep Vein ◽

The Impact

Background: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with symptomatic venous thromboembolism (VTE) from the REMOTEV registry. Methods and Results: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with direct oral anticoagulants (DOACs) or standard anticoagulation (vitamin K antagonists (VKA) or parenteral heparin/fondaparinux alone) for at least 3 months. From 1 November 2013 to 28 February 2018, among 1241 consecutive patients included, 1192 had a follow-up of at least 3 months and, among them, 1037 had PE with (727) or without DVT (310). The median age was 69 (55–80, 25th–75th percentiles). Patients with PE-associated DVT had more severe forms of PE (p < 0.0001) and, when DVT was present, proximal location was significantly correlated to PE severity (p < 0.01). However, no difference in all-cause mortality rate (hazard ratio (HR) 1.36 (CI 95% 0.69–2.92)), nor in the composite criterion of all-cause mortality and recurrence rate (HR 1.56 (CI 95% 0.83–3.10)) was noted at 3 months of follow-up. Conclusion: In REMOTEV, coexisting DVT was associated with a higher severity of PE, with no impact on short-term prognosis.

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Advantages and disadvantages of direct oral anticoagulants in older patients

Geriatric Care ◽

10.4081/gc.2018.7227 ◽

2018 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Antonio Cherubini ◽

Barbara Carrieri ◽

Paolo Marinelli

Keyword(s):

Older Patients ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Thrombin Inhibitor ◽

Vein Thrombosis ◽

Advantages And Disadvantages ◽

Gray Areas ◽

Deep Vein

Atrial fibrillation (AF) and venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, are conditions that increase with age. Anticoagulant therapy is strongly recommended both in patients with AF for the prevention of cardioembolic stroke, and for treatment of VTE and prevention of recurrent VTE. Until recently, vitamin K antagonists (VKAs) were the only oral drugs for long-term anticoagulation. In the past decade, four direct oral anticoagulants (DOACs) were approved: a direct thrombin inhibitor (dabigatran) and three factor Xa inhibitors (apixaban, rivaroxaban, edoxaban). Despite increasing evidence demonstrating the efficacy and safety of DOACs in older patients, there are still gray areas where the use of VKAs might be valuable.

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Optimal Duration of Oral Anticoagulant Therapy: A Randomized Trial Comparing Four Weeks with Three Months of Warfarin in Patients with Proximal Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649783 ◽

1995 ◽

Vol 74 (02) ◽

pp. 606-611 ◽

Cited By ~ 216

Author(s):

Mark N Levine ◽

Jack Hirsh ◽

Michael Gent ◽

Alexander G Turpie ◽

Jeffrey Weitz ◽

...

Keyword(s):

Risk Factors ◽

Deep Vein Thrombosis ◽

Randomized Trial ◽

Oral Anticoagulant ◽

Oral Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Vein Thrombosis ◽

Optimal Duration ◽

Recurrent Vte ◽

Deep Vein

SummaryThe optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin.In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.In conclusion, an IPG four weeks after proximal DVT is not a useful predictor for recurrent VTE; whereas the presence of continuing risk factors is a very strong predictor. Four weeks of oral anticoagulants may be all that is required in patients without continuing risk factors. Patients with continuing risk factors may require more than three months of oral anticoagulants.

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Gastrointestinal Bleeding: a Cardiologist's Point of View

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2021-10-01 ◽

2021 ◽

Vol 17 (5) ◽

pp. 771-778

Author(s):

O. V. Averkov ◽

L. N. Mishchenko

Keyword(s):

Gastrointestinal Bleeding ◽

Anticoagulant Therapy ◽

Oral Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Early Postoperative Period ◽

Point Of View ◽

Vein Thrombosis ◽

Coronary Syndrome

Oral anticoagulant therapy is widely used in different patients for the prevention and treatment of thromboembolic events: in atrial fibrillation, deep vein thrombosis/pulmonary embolism, acute coronary syndrome, in the early postoperative period after orthopedic surgery. Nowadays it is possible to use vitamin K antagonists (warfarin) as well as direct oral anticoagulants (DOAC): dabigatran, rivaroxaban, apixaban and edoxaban. The mai complication of any anticoagulant therapy is bleeding (gastrointestinal, intracranial, etc.), which seriously limits its usage. In this review the incidence of gastrointestinal bleeding (GIB) associated with oral anticoagulants intake was analyzed according to the results of both large randomized and postregistration trials. Furthermore, the effect of age on the risk of GIB development is discussed, and also aspects of the pathophysiology of gastrointestinal mucosa lesions in patients taking DOAC are considered.

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Safety and efficacy of direct acting oral anticoagulants and vitamin K antagonists in nonvalvular atrial fibrillation – a network meta-analysis of real-world data

VASA ◽

10.1024/0301-1526/a000746 ◽

2019 ◽

Vol 48 (2) ◽

pp. 134-147 ◽

Cited By ~ 8

Author(s):

Mirko Hirschl ◽

Michael Kundi

Keyword(s):

Real World ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Nonvalvular Atrial Fibrillation ◽

Real World Data ◽

Hazard Ratios ◽

Direct Acting ◽

Event Rates

Abstract. Background: In randomized controlled trials (RCTs) direct acting oral anticoagulants (DOACs) showed a superior risk-benefit profile in comparison to vitamin K antagonists (VKAs) for patients with nonvalvular atrial fibrillation. Patients enrolled in such studies do not necessarily reflect the whole target population treated in real-world practice. Materials and methods: By a systematic literature search, 88 studies including 3,351,628 patients providing over 2.9 million patient-years of follow-up were identified. Hazard ratios and event-rates for the main efficacy and safety outcomes were extracted and the results for DOACs and VKAs combined by network meta-analysis. In addition, meta-regression was performed to identify factors responsible for heterogeneity across studies. Results: For stroke and systemic embolism as well as for major bleeding and intracranial bleeding real-world studies gave virtually the same result as RCTs with higher efficacy and lower major bleeding risk (for dabigatran and apixaban) and lower risk of intracranial bleeding (all DOACs) compared to VKAs. Results for gastrointestinal bleeding were consistently better for DOACs and hazard ratios of myocardial infarction were significantly lower in real-world for dabigatran and apixaban compared to RCTs. By a ranking analysis we found that apixaban is the safest anticoagulant drug, while rivaroxaban closely followed by dabigatran are the most efficacious. Risk of bias and heterogeneity was assessed and had little impact on the overall results. Analysis of effect modification could guide the clinical decision as no single DOAC was superior/inferior to the others under all conditions. Conclusions: DOACs were at least as efficacious as VKAs. In terms of safety endpoints, DOACs performed better under real-world conditions than in RCTs. The current real-world data showed that differences in efficacy and safety, despite generally low event rates, exist between DOACs. Knowledge about these differences in performance can contribute to a more personalized medicine.

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Controlled Trial of the Sequential Use of Streptokinase and Ancrod in the Treatment of Deep Vein Thrombosis of Lower Limb

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649223 ◽

1977 ◽

Vol 37 (02) ◽

pp. 222-232 ◽

Cited By ~ 12

Author(s):

D. A Tibbutt ◽

C. N Chesterman ◽

E. W Williams ◽

T Faulkner ◽

A. A Sharp

Keyword(s):

Deep Vein Thrombosis ◽

Clinical Improvement ◽

Anticoagulant Therapy ◽

Lower Limb ◽

Oral Anticoagulant ◽

Controlled Trial ◽

Oral Anticoagulant Therapy ◽

Control Group ◽

Vein Thrombosis ◽

Deep Vein

SummaryTreatment with streptokinase (‘Kabikinase’) was given to 26 patients with venographically confirmed deep vein thrombosis extending into the popliteal vein or above. Treatment was continued for 4 days and the patients were allocated randomly to oral anticoagulant therapy or a course of treatment with ancrod (‘Arvin’) for 6 days followed by oral anticoagulant therapy. The degree of thrombolysis as judged by further venographic examination at 10 days was not significantly different between the 2 groups. The majority of patients showed clinical improvement but there was no appreciable difference between the groups at 3 and 6 months. Haemorrhagic complications were a more serious problem during the period of treatment with ancrod than during the equivalent period in the control group.

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