Background

The Polish Society of Internal Medicine, in collaboration with other Polish medical groups, issued comprehensive, evidence‑informed clinical practice guidelines for the prevention and treatment of venous thromboembolism (VTE).¹ Although part of a crowded field of guidelines in this clinical domain, the Polish guidelines stand out because of the wide array of topics addressed, specifically dealing with several “what if” scenarios confronting clinicians, coupled with a meticulous and rigorous guideline methodology. The aim of this commentary is to provide a practical perspective on selected issues and associated recommendations that can be considered uncertain in terms of best practices.

What is the role of acetylsalicylic acid in the prevention of venous thromboembolism after orthopedic surgery (ie, hip / knee arthroplasty, hip fracture repair)?

To provide a historical but clinically‑relevant perspective, in a randomized trial published in 1989, acetylsalicylic acid (ASA) alone was shown to be as effective as warfarin (target international normalized ratio, 2–3) for the prevention of proximal deep vein thrombosis after elective hip or knee arthroplasties.² However, its use was supplanted by the emergence of low‑molecular‑weight heparins (LMWHs) and, subsequently, direct oral anticoagulants (DOACs) as first‑line options for thromboprophylaxis after hip or knee replacement (LMWHs or DOACs) and hip fracture repair (LWMHs) surgeries.³ Over the past 1–2 decades, orthopedic surgical techniques have improved and, most importantly, patients have become fully ambulatory much sooner after surgery, thereby allowing the re‑evaluation of less intense methods of thromboprophylaxis, such as ASA, after major orthopedic surgery.

Although ASA can be combined with an initial 5‑day period of DOAC therapy after hip or knee replacement,⁴ it is uncertain if it can be used as a standalone prophylaxis regimen in such patients. Two large ongoing trials, EPCAT‑3 (VTE Prevention Following Total Hip and Knee Arthroplasty; NCT04075240) and PEPPER (Comparative Effectiveness of Pulmonary Embolism Prevention After Hip and Knee Replacement; NCT02810704), are addressing this question. In the meantime, it is sensible to limit the use of ASA‑only prophylaxis to lower‑risk patients, such as those after below‑the‑knee surgery or casting, and to combine ASA with an initial 5‑day period of a DOAC (eg, rivaroxaban 10 mg) or, empirically, a LWMH (eg, enoxaparin 40 mg) in higher‑risk patients undergoing hip / knee arthroplasty. An extended duration of DOAC or LMWH prophylaxis (ie, 14 days for knee replacement, 28 days for hip replacement) would be sensible in selected high‑risk patients who may experience limited mobility or have additional thromboembolic risk factors, such as prior VTE.

There are limited contemporary data to support the use of ASA alone for VTE prophylaxis in patients undergoing hip fracture repair, especially when compared with prophylaxis with an anticoagulant.⁵ These patients are often older, more medically complex, and with poorer mobility in the acute postoperative phase than the patients undergoing elective knee or hip arthroplasty. Until further evidence is available, we suggest caution with using ASA as the sole thromboprophylaxis agent in this setting.

According to the Polish guidelines, in patients with severe obesity, prophylaxis with higher doses of low‑molecular‑weight heparin, unfractionated heparin, or fondaparinux is preferred over standard doses. How should this statement be understood? Which specific doses should be used?

Patients with significant obesity (ie, body mass index [BMI] >35 kg/m²) are being increasingly assessed for postoperative thromboprophylaxis. There are no randomized trials comparing the efficacy and safety of “standard‑dose” vs “augmented‑dose” thromboprophylaxis in obese patients undergoing major orthopedic surgery. In general, LMWHs are sometimes favored over other agents in such patients because of the potential to administer more refined dosing, as they are available in multiple prefilled syringe doses. Using LMWHs, it is easy to implement 50% augmented dosing (eg, enoxaparin 60 mg daily, dalteparin 7500 IU daily), whereas increasing the dose of fondaparinux or a DOAC is less easy to implement. This “augmented dose” approach, though empiric, is sensible and consistent with expert‑based clinical guidance. Using DOACs without dose augmentation may also be an option in these patients, with some retrospective data showing similar thromboembolic and bleeding outcomes to those observed in individuals without significant obesity who received standard‑dose thromboprophylaxis after major arthroplasty.⁶

The Polish guidelines recommend reduced‑dose anticoagulation after 6 months of treatment; the decision whether to implement the reduction is left to the discretion of the treating physician. Is there a particular group of patients in whom the dose should not be reduced?

Managing patients who have completed 3–6 months of anticoagulant therapy following the first episode of VTE is a common scenario requiring a decision as to whether or not to continue anticoagulation with a DOAC and, if so, whether to continue a full‑dose regimen or reduce the dose. In general, management is individualized based on a patient’s estimated risk for disease recurrence coupled with patient values and preferences. Accordingly, individuals at a low risk for recurrence (<⁠4% per year), such as those with provoked (secondary) VTE and women with estrogen‑associated VTE, do not require ongoing anticoagulant therapy. In patients with idiopathic or cancer‑associated VTE, it is commonly suggested to continue anticoagulation, owing to the high VTE recurrence risk, though this decision can vary depending on several factors, including postanticoagulation D‑dimer status, presence or absence of major comorbidities, bleeding risk, and patient values and preferences. Recent trials inform practice by supporting the use of a lower‑intensity DOAC regimen (eg, rivaroxaban 10 mg daily, apixaban 2.5 mg twice‑daily), as it provides comparable efficacy and improved safety (less bleeding), as compared with a full‑dose DOAC regimen.⁷ Based on these results, many patients at a high risk for recurrent VTE likely will benefit from a lower‑intensity DOAC regimen after 6 months of anticoagulant therapy. Caution should be applied when using this strategy in patients with severe obesity (BMI >35 kg/m²), as the benefit of dose reduction was not as clear in a prespecified subgroup analysis,⁷ as well as in patients with major thrombophilia, or those who have experienced VTE on a lower‑intensity DOAC regimen in the past.

According to the Polish guidelines, the decision regarding initiation of thromboprophylaxis during pregnancy should be based on the cumulative risk factor model proposed by the Royal College of Obstetricians and Gynaecologists. Practicing physicians have noted that, according to these criteria, a patient over the age of 35, in her fourth pregnancy, with varicose veins, and a BMI greater than 30 kg/m² should receive pharmacological prophylaxis throughout the entire pregnancy. Do you think these criteria might be too strict?

Venous thromboembolism is a leading cause of morbidity and mortality in pregnancy and the postpartum period. Current guidelines recommend VTE prophylaxis in the ante- and postpartum periods for patients with previous unprovoked or hormone‑associated VTE.^8,9 Patients with high‑risk thrombophilia, particularly homozygous factor V Leiden carriers or compound heterozygotes, are also likely to benefit from ante- and postpartum prophylaxis.⁸

Deciding who else may benefit from VTE prophylaxis in the antepartum / postpartum period is challenging, especially in patients with multiple VTE risk factors of varying strengths. To facilitate decision making, scoring systems, such as the one published in the 2015 Royal College of Obstetricians and Gynaecologists guideline,⁹ have been created, incorporating various risk factors for pregnancy‑related VTE derived from previous studies. Such tools are helpful for identifying patients at a risk for VTE but are only part of an individualized anticoagulation risk‑benefit assessment. Being cognizant that some risk factors may overlap, for example, age with parity and multiple pregnancy, and recognizing that the impact of different combinations of risk factors is not fully understood is important to acknowledge when using these scoring tools. Consulting a local expert in the area is an important consideration if the role of VTE prophylaxis is not clear.

In the Polish guidelines, the section concerning thromboprophylaxis during pregnancy and the puerperium is primarily based on the recommendations of the Royal College of Obstetricians and Gynaecologists, which differ somewhat from the American Society of Hematology guidelines (Table 1). How significant are these differences, particularly with regard to the dosing method of heparin and the doses used for prophylaxis during pregnancy and the postpartum period?

Major guidelines recommend that when used, VTE prophylaxis in pregnancy should be continued during the entire pregnancy period and postpartum for 6 weeks, which is the highest‑risk period for VTE.^8,9 LMWHs are the suggested anticoagulants for VTE prophylaxis in pregnancy, as they do not cross the placenta,¹⁰ unlike DOACs, warfarin, and fondaparinux.⁸ In the postpartum period, LMWH and warfarin are suitable options, as they are considered safe in breastfeeding.^11,12 Historically, there was a debate regarding the ideal dose of LMWH in this patient population, especially given the expected weight gain during pregnancy and the high prevalence of obesity, along with increased glomerular filtration rate. A recent well‑conducted randomized study sought to address this question.¹³ It compared standard low‑dose LMWH (eg, enoxaparin 40 mg daily, and 60 mg daily if weight >100 kg) with an intermediate dose in the antepartum and postpartum phases in women deemed at a high risk for VTE during these periods based on a history of previous VTE (either unprovoked, hormone‑associated, or provoked by a minor risk factor), and demonstrated no significant difference in the rate of symptomatic VTE.¹³ As a result of this evidence, there are no strong indications to use intermediate doses of LMWH in this setting, although questions remain about patients with a very high BMI (eg, >35 kg/m²), as they were underrepresented in the study.