Factor XI inhibitors for the prevention of cardiovascular disease: A new therapeutic approach on the horizon?

Anticoagulant drugs that are currently used to prevent and/or treat thrombosis have some limitations that hinder their ability to meet specific clinical requirements. While these drugs effectively reduce the rates of thrombotic events, they simultaneously increase the risk of bleeding. Moreover, their risk-to-benefit balance is problematic in some patients, such as those with severe chronic kidney disease or those at high bleeding risk. A novel anticoagulation method, FXI inhibition has emerged as a promising alternative. It demonstrates a strong rationale for the prevention and treatment of venous thromboembolism and the potential fulfillment of unmet clinical needs in the cardiovascular field. A number of FXI inhibitors are currently undergoing clinical investigation. The objective of this review is to provide an overview of early results of research on FXI inhibitors in the cardiovascular setting, offering valuable insights into their potential role in shaping the future of anticoagulation.

Current and emerging drug strategies for the prevention of venous thromboembolism in acutely ill medical inpatients.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in patients hospitalized for acute medical illnesses. Therefore, medical inpatients require a careful VTE and bleeding risk assessment to drive optimal strategies for VTE prevention. Low molecular weight heparin and fondaparinux have long been used for inhospital prophylaxis for patients at increased risk of VTE. The selection of patients who require post-discharge prophylaxis, and the role of direct oral anticoagulants remain debated. New molecules currently under development may contribute to improve the risk benefit of VTE prevention in this setting. AREAS COVERED: This text summarizes the evidence on approved treatments and on other drugs for the prevention of VTE in acutely ill medical patients. The main focus is on their pharmacological properties, clinical efficacy and safety, and the current license approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency). The trials presented consider both inhospital and extended prophylaxis. EXPERT OPINION: Thanks to the potentially favorable safety profile, factor XI inhibitors may play a role in the prevention of VTE in this setting. The expert opinion section discusses pharmacological properties, prophylaxis trials, and potential clinical applications of this novel class of drugs.

Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism.

Preliminary data and clinical experience have suggested an increased risk of abnormal uterine bleeding (AUB) in women of reproductive age treated with anticoagulants, but solid data are lacking. The TEAM-VTE study was an international multicenter prospective cohort study in women aged 18 to 50 years diagnosed with acute venous thromboembolism (VTE). Menstrual blood loss was measured by pictorial blood loss assessment charts at baseline for the last menstrual cycle before VTE diagnosis and prospectively for each cycle during 3 to 6 months of follow-up. AUB was defined as an increased score on the pictorial blood loss assessment chart (>100 or >150) or self-reported AUB. AUB-related quality of life (QoL) was assessed at baseline and the end of follow-up using the Menstrual Bleeding Questionnaire. The study was terminated early because of slow recruitment attributable to the COVID-19 pandemic. Of the 98 women, 65 (66%) met at least one of the 3 definitions of AUB during follow-up (95% confidence interval [CI], 57%-75%). AUB occurred in 60% of women (36 of 60) without AUB before VTE diagnosis (new-onset AUB; 95% CI, 47%-71%). Overall, QoL decreased over time, with a mean Menstrual Bleeding Questionnaire score increase of 5.1 points (95% CI, 2.2-7.9), but this decrease in QoL was observed only among women with new-onset AUB. To conclude, 2 of every 3 women who start anticoagulation for acute VTE experience AUB, with a considerable negative impact on QoL. These findings should be a call to action to increase awareness and provide evidence-based strategies to prevent and treat AUB in this setting. This was an academic study registered at www.clinicaltrials.gov as #NCT04748393; no funding was received.

Intracranial bleeding risk after minor traumatic brain injury in patients on antithrombotic drugs.

BACKGROUND: Intracranial haemorrhage (ICH) risk after minor traumatic brain injury (mTBI) in patients on antithrombotic treatment is unclear. We compared ICH rates in mTBI patients on single, double and no antithrombotic therapy. Antithrombotic drugs encompassed vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) and antiplatelets. Secondary aim was to identify potential predictors of ICH. METHODS: We retrospectively analysed consecutive adults referred to our emergency department for mTBI. All clinical information was retrieved by patients' charts review. Patients were divided in 5 groups: 1) no antithrombotic users, 2) antiplatelet users, 3) vitamin K antagonist users, 4) direct oral anticoagulants users, and 5) double antithrombotic users. RESULTS: A total of 1846 patients were enrolled, mean age 71 years (IQR 46-83); 1222 (66.2%) were in group 1, 407 (22.0%) in group 2, 120 (6.5%) in group 3, 51 (2.7%) in group 4 and 46 (2.5%) in group 5. At entry, 1387 (75.1%) patients underwent brain CT, 787 (64.4%) in group 1, 387 (95.1%) in group 2, 119 (99.2%) in group 3 and 51 (100%) in group 4 and 43 (93.5%) in group 5. ICH was documented in 36 patients (4.6%; CI 95%: 3.2-6.3) in group 1, 22 (5.9%; CI 95%: 3.6-8.5) in group 2, 5 (4.2%; CI 95%: 1.4-9.5) in group 3, 2 (3.9%; CI 95%: 0.5-13.5) in group 4 and 3 (7.0%; CI 95%: 1.5-19.1) in group 5 (p-value for across groups comparison = 0.86). At multivariable analysis GCS < 15 (OR 7.95 CI 95%: 3.12-20.28), post-traumatic amnesia (OR 6.49; CI 95%:3.57-11.82), vomiting (OR 4.45 CI 95%:1.47-13.50), clinical signs of cranial fractures (OR 8.41 CI 95%: 2.12-33.33), scalp lesions (OR 2.31 CI 95%: 1.09-4.89), but none of antithrombotic drugs were independently associated with ICH. CONCLUSION: mTBI-related ICH rate was similar in patients with and without antithrombotic use. Potential predictors of ICH can be drawn from patients' clinical examination.

Antidotes for the direct oral anticoagulants: What news?

The direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulants for both stroke prevention in patients with non-valvular atrial fibrillation and the treatment and secondary prevention of venous thromboembolism. DOACs cause bleeding, albeit less than warfarin. Most bleeding complications can be controlled by general reversal strategies and supportive care. However, in case of life-threatening bleeding, or when urgent invasive procedures are needed, a more rapid and thorough reversal may be required. Idarucizumab, andexanet alfa and ciraparantag have been developed as reversal agents for the DOACs. To date idarucizumab is the only approved antidote and is specific for dabigatran. Andexanet alfa, a reversal agent for the factor Xa inhibitors, is still under investigation, but its approval by regulatory agencies is expected soon. Ciraparantag, a universal antidote, is in an earlier stage of development. Based on the results of clinical trials to date, these compounds appear to be breakthrough for urgent and emergency reversal. When administered at fixed doses, they ensured a rapid, efficient and safe restoration of haemostasis. From a practical perspective, all hospitals should develop local protocols to ensure safe and efficient clinical implementation of reversal strategies. Post-marketing studies will be essential to assess the evolution of management strategies and to confirm the safety and effectiveness of these agents.

Optimal treatment duration of venous thrombosis.

Randomized controlled trials have shown that patients with venous thromboembolism benefit from a minimum of three months of anticoagulant therapy. After this period, it was suggested that patients with an expected annual recurrence rate of < 5% could safely discontinue treatment. Using a population-based approach for stratification, these patients are those with major transient risk factors, and represent the minority. For all other patients, including those with previous episodes of venous thromboembolism, cancer, or unprovoked events, this treatment duration may not be sufficiently protective. Because extending anticoagulation for additional three to nine months does not result in further, long-term reduction of recurrences, indefinite treatment duration should be considered. However, case-fatality rate for major bleeding in patients taking warfarin for more than three months is higher than case-fatality rate of recurrent venous thromboembolism. Thus, an individual patient approach to improve and increase the identification of those who can safely discontinue treatment at three months becomes necessary. Clinical prediction rules or management strategies based on D-dimer levels or residual vein thrombosis have been proposed and need further refinement and validation. Specific bleeding scores are lacking. Meanwhile, the oral direct inhibitors have been proposed as potential alternatives to the vitamin K antagonists, and aspirin may provide some benefit in selected patients who discontinue anticoagulation. Deep vein thrombosis in unusual sites is associated with less, but potentially more severe recurrences, in particular in patients with splanchnic vein thrombosis who also face an increased risk of bleeding complications while on treatment.

Risk of recurrence of unusual site venous thromboembolism.

The term unusual site venous thrombosis defines uncommon clinical manifestations of venous thromboembolism occurring in sites different from the lower limbs or the lungs, with peculiar pathophysiological features and clinical history. Information on long-term outcomes of unusual site thrombosis is generally scant, because most studies are small and usually retrospective. Recurrence rate of cerebral vein thrombosis is about 2/100 patient-years; the only identified predisposing factors have been male gender and personal history of thrombosis. Retinal vein occlusion showed a recurrence in the same eye of 2.5% and in the fellow eye of 11.9% within four years. Hypercholesterolemia, hypertriglyceridaemia and hyperhomocysteinaemia were significantly associated with recurrent events. Recurrence rates of splanchnic vein thrombosis are difficult to estimate given the heterogeneity of patient populations; higher recurrence rates are reported in the cirrhotic population (from 27% to 38.5%). Hormone therapy, myeloproliferative neoplasm or other prothrombotic states, and absence of anticoagulant therapy emerged as independent prognostic factors. Future studies should aim at better assessing the risk of recurrence in different patients subgroups and at identifying more accurate prognostic markers.

Prognostic clinical prediction rules to identify a low-risk pulmonary embolism: a systematic review and meta-analysis.

BACKGROUND: Prognostic assessment is important for the management of patients with a pulmonary embolism (PE). A number of clinical prediction rules (CPRs) have been proposed for stratifying PE mortality risk. The aim of this systematic review was to assess the performance of prognostic CPRs in identifying a low-risk PE. METHODS: MEDLINE and EMBASE databases were systematically searched until August 2011. Derivation and validation studies that assessed the performance of prognostic CPRs in predicting adverse events-risk in PE patients were included. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I(2) statistics. RESULTS: Of 1125 references in the original search, 33 relevant articles were included. Nine CPRs were assessed in 37 cohorts, for a total of 35,518 patients. Pulmonary Embolism Severity Index and prognostic Geneva CPR were investigated in 22 and 6 cohorts, respectively. Eleven (29.7%) cohorts were of high quality. The median follow-up was 30 days. In low-risk PE patients, pooled short-term mortality (within 14 days or less) was 0.7% (95% CI 0.3-1.1%, random-effects model; I(2) = 49.6%), 30-day mortality was 1.7% (95% CI 1.1-2.3%, random-effects model; I(2) = 82.4%) and 90-day mortality was 2.2% (95% CI 1.2-3.4%, random-effects model; I(2) = 59.8%). CONCLUSIONS: Prognostic CPRs efficiently identify PE patients at a low risk of mortality. Before implementing prognostic CPRs in the routine care of PE patients, well-designed management studies are warranted.

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis.

BACKGROUND: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease. OBJECTIVES: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence-based guidelines. PATIENTS/METHODS: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0-3.5, and ASA, 50-650 mg daily, with at least 3 months of follow-up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model. RESULTS: Four thousand four hundred and forty-two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83-1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71-3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61-1.75). Minor bleeding, from a 1748-patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13-2.00). CONCLUSIONS: This meta-analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0-3.5, and ASA, 50-650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.