Recent Advances in Thrombosis and Hemostasis: Part VI

With the new day comes new strength and new thoughts.

Eleanor Roosevelt, 1884–1962

In this sixth themed issue of the series of Recent Advances in Thrombosis and Hemostasis, half of the contributions relate to the topic of direct oral anticoagulants (DOACs). We still continue to see manuscripts submitted using the term “novel” anticoagulants. Most of us agree that after 10 years from their first approval, they are not so novel anymore. Some still read out the abbreviation NOAC as “novel oral anticoagulants,” but the current correct spell-out is “non–vitamin K antagonist oral anticoagulants.” This term and abbreviation have been chosen from the start of this theme series to be the standard (rather than DOAC), thus creating a level of harmonization. Among referring physicians to our Thrombosis Service, I see the two terms used about equally, and anyone is free to use whichever they prefer, but I personally find it annoying to see, for example, within the same PowerPoint presentation the two terms used in a random mix.

Another detail we have to correct far too often is the number of active digits in proportions, p-values and confidence intervals. To see in a study of 160 patients with 80 in each of two groups, comparison with a p-value of 0.367 or of 0.0245, as well as the number of females = 37 (46.2%), is ludicrous. It gives a false impression of very high precision. Moreover, for nonsignificant p-values, it is sufficient to show only one active digit, since a p-value of 0.367 does not give any more information than p = 0.4—it still statistically nonsignificant.

This theme issue starts with two papers on oral contraceptives and venous thromboembolism. The first contribution is a review written as a commitment to completing the requirements of Eberhard Mammen Young Investigator Award recipients by Khialani from Frits Rosendaal's group in Leiden.[1] In addition to well-known data regarding the increased risk of thrombosis with the estrogen component, as well as with third-generation progestogens, the comparatively low risk of levonorgestrel, even in women with inherited thrombophilia, is discussed. Furthermore, the authors raise the interesting hypothesis that after a switch from one oral contraceptive to another, there might be a spike in the incidence of venous thromboembolism since the individual susceptibility to different hormonal agents could vary. They also discuss the lack of related, validated risk assessment models (RAMs).

The second paper on oral contraceptives, by Douxfils et al, also an Eberhard Mammen Young Investigator Award recipient in 2019, also on behalf of some collaborators, goes deeper into the associated risk assessment, focusing on the thrombogenic status in the patient and in the population before and after starting on a contraceptive.[2] The endogenous thrombin potential for the assessment of normalized activated protein C resistance has shown preliminary promising predictive value in this respect.

Moving on from one risk factor theme to another, Tang et al have further analyzed a cohort of more than 4,000 patients with pulmonary embolism,[3] for which they previously presented in Seminars in Thrombosis and Hemostasis data on the use of the CHADS₂ score to predict outcome.[4] Pulmonary embolism can be a result of atrial fibrillation due to stagnation of blood in the right atrium, and, conversely, pulmonary embolism can generate atrial fibrillation through hemodynamic effects with distention of the myocardium or through neurohormonal effects.[4] Whether new-onset atrial fibrillation in patients with pulmonary embolism could lead to worse outcomes is the focus in the current analysis.

On a related topic, Anfinogenova et al have reviewed the risk factors, epidemiology, diagnostic options, and management for right atrial thrombus.[5] The authors also present a RAM for the development of thrombus in the right atrial appendage.

Sulodexide is a glycosaminoglycan with antithrombotic and anti-inflammatory effects, among others. Bikdeli et al have performed a meta-analysis of randomized controlled trials in which sulodexide was compared with placebo (or nothing) for different indications.[6] Since only six studies were identified and there were five different indications, it is clear that the arising meta-analysis has several limitations. However, the outcomes of mortality, myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, and “bleeding events” were investigated in the majority of the studies. The authors were able to identify a significant reduction in myocardial infarction and in deep vein thrombosis, and the increase in bleeding events with sulodexide was not statistically significant.

Mian et al then entertain the reader with a bibliometric analysis of research on anticoagulation published during the past 25 years.[7] They describe characteristics of the 100 most cited articles, after excluding basic science, reviews, and clinical practice guidelines. Unsurprisingly, frequently cited publications on NOACs have been increasing at a 3.4-fold faster rate than other topics on anticoagulation.

This leads us to the second half of the contributions to this theme issue. The studies on NOACs in the aforementioned analysis[7] were generally phase III clinical trials, which excluded certain risk groups and included very few of the patients with extreme characteristics such as with morbid obesity. Abildgaard et al have performed a systematic literature review of 72 studies on different anticoagulants with respect to recommended dose regimens for the obese, defined as body mass index (BMI) ≥ 30 kg/m² or body weight ≥ 100 kg.[8] They summarize the results both for prophylactic use and for therapeutic dosing.

From clinical trials over to clinical practice, Russo et al have used a database from two Italian cardiology centers to analyze outcomes of anticoagulation over a 5-year period in patients with atrial fibrillation and body mass index ≥ 30 kg/m².[9] They identified 248 patients on NOAC and 496 patients on vitamin K antagonist (VKA), with similar mean BMI of 35. Those treated with a NOAC had a lower risk of major bleeding and similar risk of thromboembolic events as those on VKAs. Predictors for these outcomes were also analyzed.

Superficial thrombophlebitis is sometimes treated with topical or oral anti-inflammatory agents. In case of progression on this treatment, or for extensive thrombophlebitis, low-molecular-weight heparin or fondaparinux has typically been the treatment of choice. The SURPRISE study, published in 2017, showed that rivaroxaban at a dose of 10 mg daily was noninferior to fondaparinux regarding efficacy.[10] Another randomized study (RASET) comparing the same dose of rivaroxaban with placebo, on top of optional anti-inflammatory treatment, was initiated by Kearon et al in 2015. Due to slow recruitment, it was stopped in December 2017, and the results are presented here.[11] Although only 85 of 600 planned patients were recruited, the results from RASET add information to the SURPRISE study since the design was different. Versus placebo, treatment with rivaroxaban resulted in greater improvement of leg pain by 90 days, and the treatment failures were numerically lower with the latter (1 vs. 5 on placebo) although not statistically significant.

In the last full paper, another Eberhard Mammen Young Investigator Award recipient, Schreuder et al provide a beautifully illustrated review of current reversal agents for the direct factor Xa inhibitors.[12] They also explain how future antidotes are developed and will work. This is indeed an enjoyable final reading of the composite 10 papers in this issue.

We have also included two letters of correspondence in this issue of the journal. The first, by Cattaneo et al, is a single-center observational study of 50 patients with human immunodeficiency virus infection receiving anticoagulation (mainly with VKAs; 82%).[13] The proportion with potential drug–drug interactions (orange flag) was 58% but would have been 42% if all patients were to receive an NOAC.

The second letter, by Udut et al, discusses the different disturbances in coagulation, platelet function, and fibrinolysis that they have detected in patients with vestibuloatactic syndrome, comparing those with and without vestibular hypofunction and against controls.[14] Several of the tests of hemostatic functions are abnormal and more so in the group with vestibular hypofunction, which begs the question whether anticoagulants would reduce the risk of chronic cerebral ischemia.

In summary, this issue contains a variety of interesting presentations of different thromboembolic conditions as well as several important aspects of the NOACs. Hopefully many, if not all, contributions will attract and delight our readers.

Publication History

Article published online:
23 December 2020

• References

• 1 Khialani D, Rosendaal FR, van Hylckama Vlieg A. Hormonal contraceptives and the risk of venous thrombosis. Semin Thromb Hemost 2020; 46 (08) 865-871
• 2 Douxfils J, Maurimont L, Bouvy C. Oral contraceptives and venous thromboembolism: focus on testing that may enable prediction and assessment of the risk. Semin Thromb Hemost 2020; 46 (08) 872-886
• 3 Tang RB, Jing YY, Xu ZY. et al. New-onset atrial fibrillation and adverse in-hospital outcome in patients with acute pulmonary embolism. Semin Thromb Hemost 2020; 46 (08) 887-894
• 4 Tang RB, Xu ZY, Avula UMR. et al. Risk stratification for acute pulmonary embolism in patients with atrial fibrillation: role of CHADS₂ score. Semin Thromb Hemost 2017; 43 (08) 864-870
• 5 Anfinogenova YJ, Vasiltseva OY, Vrublevsky AV. et al. Right atrial thrombosis and pulmonary embolism: a narrative review. Semin Thromb Hemost 2020; 46 (08) 895-907
• 6 Bikdeli B, Catterjee S, Kirtane AJ. et al. Sulodexide versus control and the risk of thrombotic and hemorrhagic events: meta-analysis of randomized trials. Semin Thromb Hemost 2020; 46 (08) 908-918
• 7 Mian M, Sreedharan S, Limaye NS. et al. Research trends in anticoagulation therapy over the last 25 years. Semin Thromb Hemost 2020; 46 (08) 919-931
• 8 Abildgaard A, Madsen SA, Hvas AM. Dosage of anticoagulants in obesity: recommendations based on a systematic review. Semin Thromb Hemost 2020; 46 (08) 932-969
• 9 Russo V, Bottino R, Rago A. et al. Clinical performance of direct oral anticoagulants in real-world obese patients with atrial fibrillation. Semin Thromb Hemost 2020; 46 (08) 970-976
• 10 Beyer-Westendorf J, Schellong SM, Gerlach H. et al; SURPRISE Investigators. Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial. Lancet Haematol 2017; 4 (03) e105-e113
• 11 Kearon C, Carrier M, Gu C. et al. Rivaroxaban compared to placebo for the treatment of leg superficial vein thrombosis: a randomized trial. Semin Thromb Hemost 2020; 46 (08) 977-985
• 12 Schreuder M, Reitsma PH, Bos MHA. Reversal agents for the direct factor Xa inhibitors: biochemical mechanisms of current and newly emerging therapies. Semin Thromb Hemost 2020; 46 (08) 986-998
• 13 Cattaneo D, Formenti T, Gidaro A, Merlo A, Gervasoni C. Use of direct oral anticoagulants in people living with HIV: a single-center experience. Semin Thromb Hemost 2020; 46 (08) 999-1001
• 14 Udut VV, Udut EV, Kingma H, Demkin VP, Kotlovskaya LY, Shchetinin PP. Disturbances of hemostasis with vestibulo-atactic complications of chronic cerebral ischemia. Semin Thromb Hemost 2020; 46 (08) 1002-1006