by Donna Castellone, MS, MT (ASCP) SH •
August 08, 2022
The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation. Please Note: many linked teasers require account/subscription in order to view full articles.
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Two randomized trials that looked at the routine use of antithrombotic therapies to prevent thromboembolic complications provided no benefit for symptomatic outpatients with COVID-19. The OVID trial found that the 30 day risk of hospitalization and death was similar among patients who received enoxaparin for 14 days versus those who received standard of care. While in the ETHIC trial no difference was found in the all-cause mortality and hospitalization at 21 days between patients who received enoxaparin once or twice daily versus standard of care group. Both of these trials aligned with the North American ACTIV-4B trial which showed that antithrombotic therapy with either aspirin or apixaban did not reduce the rate of a composite outcome of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization as a result of cardiovascular or pulmonary causes compared with placebo.
The utility of antithrombotic treatments to aid in the prevention of respiratory failure and mortality have generally shown little if any role for antithrombotics despite COVID-19 being a highly prothrombotic viral disease causing arterial and venous thromboembolic events.
Based on data from more than 600,000 women evidence shows that there is an association between pregnancy complications and the later risk of both nonfatal and fatal stroke. However, prior studies on infertility, miscarriage or still birth have generated mixed results. When eight observational studies were reviewed that included 618,851 women who had information on infertility, miscarriage or stillbirth records were analyzed for risk for first fatal or nonfatal stroke. The median follow up period was 13 years for non-fatal stroke and 9.4 years for fatal stroke. Results showed that 17.2% experience infertility, 16.6% miscarriage and 4.6% had a still birth.
In women with a history of infertility there was a significantly higher nonfatal stroke risk when compared with those without infertility. When looking at stroke subtypes there was an increased association between miscarriage and ischemic stroke. Nonfatal stroke was also increased in those with a history of miscarriage. The risk increased with the number of miscarriages. Those who had 3 or more miscarriages had a higher risk for ischemic or hemorrhagic stroke. They were also at an increased risk for fatal stroke. There was a 31% increased risk of nonfatal stroke in women with a history of stillbirth. There was also an increased risk in fatal stroke risk.
The reason for the increased stroke risk may potentially be endothelial dysfunction associated with pregnancy. This may cause placentation-related defects which may persists after a complicated pregnancy. It may contribute to reduced vasodilation and proinflammatory status, as well as prothrombic properties resulting in a risk factor for stroke in women. Risk mitigation would include monitoring these women for risk factors such as high blood pressure, blood sugar and lipid levels.
Limitations of the study included using questionnaires to collect information and the variation in definitions of infertility, miscarriage and stillbirth. There was incomplete data on stroke subtypes and covariate adjustments such as thyroid disease and endometriosis. However, it was a large, diverse study population. The study did not evaluate why patients experienced infertility, recurrent pregnancy loss or still birth. It is important to look at underlying medical conditions that could be treated and may reduce complications and future risk of stroke.
Korean ACS patients who were started and remained on prasugrel after PCI did not have any rates of major adverse cardiac and cerebrovascular events when compared with those on another P2Y12 inhibitor. They were switched to prasugrel because they needed a more potent antiplatelet agent. This cohort of patients are more prone to bleeding and may not achieve the benefit from dual antiplatelet therapy and many South Korean physicians are reluctant to use them. Primary endpoint was cardiovascular death, nonfatal MI or stroke, major bleeding unrelated to CABG.
There were 3077 patients older than 19 and 23.6% were in the naïve cohort and 76.4% in the switch cohort. Mean age was 60.6 years and 25.2% were diagnosed with ST-segment elevation MI. More than half of the switch cohort converted to prasugrel from clopidogrel and 27.7% switched from ticagrelor to prasugrel because of poor compliance with twice daily dosing.
After 1 year, 1.8% of patients experienced at least one MACCE, however the rate was similar 1.7% in the naïve cohort. The switch cohort was not associated with a higher risk for MACCE. There also was no difference in rates of adverse drug reaction. The biggest limitation of this study was a lack of a control group. Since some of the subgroups were small, robust statistical analysis was not possible.
The immune response triggered by COVID-19 has been studied by the NIH. The proteins that respond to viruses attack the cells lining the brain's blood vessels which lead to inflammation and damage. This may lead to short and long term neurological symptoms. The SARS-CoV-2 infection causes platelet to stick together and form clots while blood proteins also leak from the blood vessels leading to inflammation and destruction of neurons.
After examining the brain changes in nine people who died after contracting the virus it was discovered that antibodies attack the lining of the brain's blood vessels leading to inflammation and damage. The virus was not detected in the patient's brains suggesting the virus was not infecting the brain directly. This can help in the development of therapies for COVID-19 in patients who have lingering neurological symptoms.
The antibodies that are produced in response to COVID-19 may mistakenly target cells crucial to the blood brain barrier. Damaging the endothelial cells that form this barrier can lead to leakage of proteins from the blood which can cause either bleeding or clotting and increase the risk of stroke. These immune complexes were found on the surface of the endothelial cells in COVID patients.
The brain tissue from nine patients were compared to 10 controls. Tissue was looked at for neuroinflammation and immune responses using immunohistochemistry. Evidence was found that damage to endothelial cells was likely due to an immune response. The formation of clots cause leakage to occur and as a result macrophages can come to repair the damage, resulting in inflammation which can cause damage to neurons. In the areas that had damage to the endothelial cells more than 300 gene showed decreased expression with six genes being increased. These were associated with oxidative stress, DNA damage and metabolic dysregulation which may provide insight as to the molecular basis of neurological symptoms and offer possible therapeutic targets.
Since the SARs-CoV-2 virus is not detected in the brain it is unclear what antige the immune response targets. Possibly it is the antibodies against the SARs-CoV-2 spike protein could bind to the ACE2 receptor used by the virus to enter cells.
Researchers have linked patients with traumatic brain injury with a history of taking vitamin K antagonists (VKA) are more likely to die or need acute neurosurgery in the month following the injury. Worse outcomes were also associated with preinjury use of DOACs, but not as high as VKA, while ADP inhibitors were not linked to higher rates of death or surgery.
Older adults (60 years and older) are expected to make up 22% of the world's population by 2040, which is double what it was in 2015. They are also at a higher risk for AF and cardioembolic events which means higher utilization of OAC making them at a higher risk for TBI by increasing the risk of intracranial hemorrhage.
Data from 57,056 patients diagnosed with mild TBI or concussion were investigated. DOACs were given in 0.9% of patients, 7.1% VKA and 2.3% ADP inhibitors. Mortality at 30 days was 15.4% in the VKA group, 8.4% in the DOAC group, and 7.1% in patients without OAC. Patients who were also treated with VKA were at a significantly higher risk for death within 30 days versus those without OAC. ADP inhibitors were not associated with mortality, and mortality was not significantly different between patients on DOAC and those without any oral anticoagulation. Patients taking VKA were significantly more likely to need acute neurosurgery than patients without OAC.
The trials for DOACs often excluded patients with aortic valve disease. There is evidence that VKA compared to DOACs can aggravate progression of valvular calcification and possibly curtail survival. In patients on warfarin the rate of mortality went up by a third compared with those not on OAC. Aortic valves appear to deteriorate faster for those on warfarin than DOACs. Results were obtained on 2383 patients 60 years or older diagnosed with mild to moderate aortic stenosis of whom 30% were on OAC.
While the study is unable to show cause and effect it is the largest study to reveal the strong association of warfarin relative to DOAC therapy with faster disease progression and poorer clinical outcomes in mild or moderate aortic stenosis. These are only observational findings and should be interpretated with caution and require randomized comparisons.
However, there is still a large mortality rate associated with warfarin when compared with DOACs as well as almost a 40% reduction risk in aortic valve replacement for DOACs despite there being evidence of progression of valve disease in this group.
There is still little known about the mechanism leading to multi-organ damage in COVID-19. It is clear that it doesn't only affect the pulmonary system but can also cause damage to several other organs as seen in patients who present with severe arterial and venous thromboembolic events. Incidences of pulmonary embolism, myocardial infarction, and stroke have been observed in both mild and severe disease. Additionally a hypercoagulable state with abnormal coagulation parameters have been described. It has been suggested that COVID-19 could dysregulate the vascular homeostasis especially in high risk patients. COVID-19 induced coagulopathy is a common condition with mostly remains subclinical.
Thrombocytes may play a leading role in the multi-organ damage that is seen in the SARS-CoV-2 infection which leads to thrombus formation and disseminated ischaemia. The presence of microvascular thrombi in many organs containing neutrophils linking thrombo-immune dysregulation and the thromboembolic events as well as increased platelet reactivity. Patients expressed higher levels of important transmembrane adhesion proteins and receptors. This could contribute to the coagulopathy observed in COVID-19.
Observation has hypothesized that platelet activation could result from a direct effect of the virus on thrombocytes but a viral transfection into thrombocytes still has not been demonstrated. An investigation showed that the viral spike protein S stimulated human platelets to release prothrombotic factors and induces the formation of platelet leucocyte aggregate even in the absence of the virus.
After two years, the actual pathophysiology of COVID-19 still needs to be explained but anucleated platelets may play an important role in severely ill patients and may be the key to reducing the cardiovascular burden of COVID-19.
Based on findings from the nursers' cohort study women with endometriosis carry an elevated stroke risk for the rest of their lives. The greatest risk was found in those that had a hysterectomy and oophorectomy. The study included 112,056 women followed from 1989 until 2017. There were 893 (<1%) incidences of stroke with laparoscopically confirmed endometriosis reported in 5244 women and 93% of the cohort were white. There was a 34% greater risk of stroke in these women. Previous studies have shown an increased risk in cardiovascular disease, heart attack, angina and atherosclerosis which appear to peak at an earlier age. However, no age difference was found for stroke risk.
Overall, the risk is low but supports evidence that whole health care for these women is important and should be aware of stroke risk.
In a phase I/II study that included 10 men with severe or moderately severe hemophilia A who received one of four doses of FLT 180a (verbrinacogene setparvovec). FLT180a is a liver-directed adeno-associated virus gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B.
Results showed that all had a dose dependent increase in factor IX levels. This was sustained in 9/10 patients with a median follow up of 27.2 months which eliminated the need for factor IX prophylaxis Levels of factor IX showed that five patients had normal factor IX levels (50-150%), ranging from 51% to 78%, while three patients had levels below the normal range (23-43%). One patient who was given the highest dose had higher than normal levels (260%). Median bleeding rates prior to gene therapy was 2.93 events per year compared with 0.71 events after.
Adverse events were reported in 10% of patients and 24% were related to immunosuppression. Most common related event was an increase in lever aminotransferase. Also, in the patient who developed a very high level of FIX developed thrombosis and required anticoagulant medication.
Further evaluation is needed to confirm the dose and immunosuppressive regimen to maintain hemostasis in hemophilia B patients and to evaluate safety.
Diana Aguiar de Sousa, MD, PhD; Michele Romoli, MD; Mayte Sánchez Van Kammen, MD; Mirjam R. Heldner, MD, MSc; Andrea Zini, MD; Jonathan M. Coutinho, MD, PhD; Marcel Arnold, MD; José M. Ferro, MD, PhD
Background: Cerebral venous thrombosis (CVT) has recently been reported as a common thrombotic manifestation in association with vaccine-induced thrombotic thrombocytopenia, a syndrome that mimics heparin-induced thrombocytopenia (HIT) and occurs after vaccination with adenovirus-based SARS-CoV-2 vaccines. We aimed to systematically review the incidence, clinical features, and prognosis of CVT occurring in patients with HIT.
Methods: The study protocol was registered with PROSPERO (CRD42021249652). MEDLINE, EMBASE and Cochrane CENTRAL were searched up to June 1, 2021 for HIT case series including >20 patients, or any report of HIT-related CVT. Demographic, neuroradiological, clinical, and mortality data were retrieved. Meta-analysis of proportions with random-effect modeling was used to derive rate of CVT in HIT and in-hospital mortality. Pooled estimates were compared with those for CVT without HIT and HIT without CVT, to determine differences in mortality.
Results: From 19073 results, we selected 23 case series of HIT (n=1220) and 27 cases of HIT-related CVT (n=27, 71% female). CVT developed in 1.6% of 1220 patients with HIT (95% CI,1.0%–2.5%, I 2=0%). Hemorrhagic brain lesions occurred in 81.8% of cases of HIT-related CVT and other concomitant thrombosis affecting other vascular territory was reported in 47.8% of cases. In-hospital mortality was 33.3%. HIT-related CVT carried a 29% absolute increase in mortality rate compared with historical CVT controls (33.3% versus 4.3%, P<0.001) and a 17.4% excess mortality compared with HIT without CVT (33.3% versus 15.9%, P=0.046).
Conclusions: CVT is a rare thrombotic manifestation in patients with HIT. HIT-related CVT has higher rates of intracerebral hemorrhage and a higher mortality risk, when compared with CVT in historical controls. The recently reported high frequency of CVT in patients with vaccine-induced thrombotic thrombocytopenia was not observed in HIT, suggesting that additional pathophysiological mechanisms besides anti-platelet factor-4 antibodies might be involved in vaccine-induced thrombotic thrombocytopenia-related CVT.
Aims: Aspirin is widely used in cardiovascular disease prevention but is also associated with an increased risk of bleeding. The net effect of aspirin on dementia and cognitive impairment is uncertain.
Methods and Results: In the ASCEND trial, 15 480 people from the UK with diabetes and no history of cardiovascular disease were randomized to aspirin 100 mg daily or matching placebo for a mean of 7.4 years. The 15 427 ASCEND participants with no recorded dementia prior to baseline were included in this cognitive study with a primary pre-specified outcome of 'broad dementia', comprising dementia, cognitive impairment, or confusion. This was ascertained through participant, carer, or general practitioner report or hospital admission diagnosis, by 31 March 2019 (~2 years beyond the scheduled treatment period). The broad dementia outcome occurred in a similar percentage of participants in the aspirin group and placebo group: 548 participants (7.1%) vs. 598 (7.8%), rate ratio 0.91 [95% confidence interval (CI), 0.81–1.02]. Thus, the CI excluded proportional hazards of >2% and proportional benefits of >19%.
Conclusion: Aspirin does not have a large proportional effect on the risk of dementia. Trials or meta-analyses with larger total numbers of incident dementia cases to increase statistical power are needed to assess whether any modest proportional 10–15% benefits of 5–7 years of aspirin use on dementia exist.
US Preventive Services Task Force; Karina W Davidson , Michael J Barry , Carol M Mangione , Michael Cabana , David Chelmow , Tumaini Rucker Coker , Esa M Davis , Katrina E Donahue , Carlos Roberto Jaén , Alex H Krist , Martha Kubik , Li Li , Gbenga Ogedegbe , Lori Pbert , John M Ruiz , James Stevermer , Chien-Wen Tseng , John B Wong
JAMA 2022 Apr 26;327(16):1577-1584
Importance: Cardiovascular disease (CVD) is the leading cause of mortality in the US, accounting for more than 1 in 4 deaths. Each year, an estimated 605 000 people in the US have a first myocardial infarction and an estimated 610 000 experience a first stroke.
Objective: To update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD. The systematic review also investigated the effect of aspirin use on colorectal cancer (CRC) incidence and mortality in primary CVD prevention populations, as well as the harms (particularly bleeding) associated with aspirin use. The USPSTF also commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level.
Population: Adults 40 years or older without signs or symptoms of CVD or known CVD (including history of myocardial infarction or stroke) who are not at increased risk for bleeding (eg, no history of gastrointestinal ulcers, recent bleeding, other medical conditions, or use of medications that increase bleeding risk).
Evidence assessment: The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit. The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults 60 years or older has no net benefit.
Recommendation: The decision to initiate low-dose aspirin use for the primary prevention of CVD in adults aged 40 to 59 years who have a 10% or greater 10-year CVD risk should be an individual one. Evidence indicates that the net benefit of aspirin use in this group is small. Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit. (C recommendation) The USPSTF recommends against initiating low-dose aspirin use for the primary prevention of CVD in adults 60 years or older. (D recommendation).
Thomas J. Cahill, MB, BS, DPhil1; Ajay J. Kirtane, MD, SM1; Martin Leon, MD1; et alSusheel K. Kodali, MD1
JAMA Cardiol. Published online June 22, 2022.
Importance Subclinical leaflet thrombosis affects approximately 15% of patients after transcatheter aortic valve replacement (TAVR). The pathophysiology and clinical significance of leaflet thrombosis remain incompletely understood. Defining the optimal management strategy in patients who are asymptomatic, including the role for oral anticoagulation (OAC), is a key challenge for the field.
Observations Three recent randomized trials have evaluated the role of OAC in patients after TAVR. These studies have confirmed prior observational data suggesting that OAC is effective at prevention of subclinical leaflet thrombosis. Overall, however, OAC does not lead to a clinical benefit over the period studied, and in some patients may be harmful owing to bleeding risk.
Conclusions and Relevance Strategies for identification of patients in whom the benefit of OAC outweighs the risks are required for optimization of long-term outcome after TAVR. This requires clearer insights into the mechanisms of asymptomatic leaflet thrombosis, its clinical significance, and patient-specific risks of bleeding and structural valve degeneration.
Behnood Bikdeli, MD, MS1,2,3; César Caraballo, MD2; Javier Trujillo-Santos, MD, PhD4; et alJean Philippe Galanaud, MD, PhD5; Pierpaolo di Micco, MD, PhD6; Vladimir Rosa, MD, PhD7; Gemma Vidal Cusidó, MD8; Sebastian Schellong, MD, PhD9; Meritxell Mellado, MD, PhD10; María del Valle Morales, MD11; Olga Gavín-Sebastián, MD, PhD12; Lucia Mazzolai, MD, PhD13; Harlan M. Krumholz, MD, SM2,14,15; Manuel Monreal, MD, PhD16,17,18; for the RIETE Investigators
JAMA Cardiol. Published online July 13, 2022.
Importance Insufficient data exist about the clinical presentation, short-term, and long-term outcomes of patients with isolated distal deep vein thrombosis (IDDVT), that is, thrombosis in infrapopliteal veins without proximal extension or pulmonary embolism (PE).
Objective To determine the clinical characteristics, short-term, and 1-year outcomes in patients with IDDVT and to compare the outcomes in unadjusted and multivariable adjusted analyses with patients who had proximal DVT.
Design, Setting, and Participants This was a multicenter, international cohort study in participating sites of the Registro Informatizado Enfermedad Tromboembólica (RIETE) registry conducted from March 1, 2001, through February 28, 2021. Patients included in this study had IDDVT. Patients with proximal DVT were identified for comparison. Patients were excluded if they had a history of asymptomatic DVT, upper-extremity DVT, coexisting PE, or COVID-19 infection.
Main Outcomes and Measures Primary outcomes were 90-day and 1-year mortality, 1-year major bleeding, and 1-year venous thromboembolism (VTE) deterioration, which was defined as subsequent development of proximal DVT or PE.
Results A total of 33 897 patients were identified with isolated DVT (without concomitant PE); 5938 (17.5%) had IDDVT (mean [SD] age, 61  years; 2975 male patients [50.1%]), and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65  years; 14 315 male patients [51.2%]). Compared with individuals with proximal DVT, those with IDDVT had a lower comorbidity burden but were more likely to have had recent surgery or to have received hormonal therapy. Patients with IDDVT had lower risk of 90-day mortality compared with those with proximal DVT (odds ratio [OR], 0.47; 95% CI, 0.40-0.55). Findings were similar in 1-year unadjusted analyses (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59) and adjusted analyses (HR, 0.72; 95% CI, 0.64-0.82). Patients with IDDVT had a lower 1-year hazard of VTE deterioration (HR, 0.83; 95% CI, 0.69-0.99). In 1-year adjusted analyses of patients without an adverse event within the first 3 months, IDDVT was associated with lower risk of VTE deterioration (adjusted HR, 0.48; 95% CI, 0.24-0.97). By 1-year follow-up, symptoms or signs of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%).
Conclusions and Relevance Results of this cohort study suggest that patients with IDDVT had a less ominous prognosis compared with patients with proximal DVT. Such differences were likely multifactorial, including the differences in demographics, risk factors, comorbidities, particularly for all-cause mortality, and a potential association of thrombus location with VTE deterioration and postthrombotic syndrome. Randomized clinical trials are needed to assess the optimal long-term management of IDDVT.
Behnood Bikdeli, MD, MS1,2,3,4; Farbod Zahedi Tajrishi, MD5; Parham Sadeghipour, MD6,7; et alAzita H. Talasaz, PharmD8,9; John Fanikos, RPH, MBA10; Giuseppe Lippi, MD11; Deborah M. Siegal, MD, MSc12; John W. Eikelboom, MBBS13; Manuel Monreal, MD, PhD14; David Jimenez, MD, PhD15; Jean M. Connors, MD16; Walter Ageno, MD, PhD17; Geoffrey D. Barnes, MD, MSc18; Gregory Piazza, MD, MS1,2; Dominick J. Angiolillo, MD, PhD19; Sahil A. Parikh, MD4,20; Ajay J. Kirtane, MD, SM4,20; Renato D. Lopes, MD, PhD21,22; Deepak L. Bhatt, MD, MPH1; Jeffrey I. Weitz, MD23,24; Roxana Mehran, MD25; Harlan M. Krumholz, MD, SM3,26,27; Samuel Z. Goldhaber, MD1,2; Gregory Y. H. Lip, MD28,29
JAMA Cardiol. 2022;7(7):747-759.
Importance Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.
Observations Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.
Conclusions and Relevance Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.