Everything the clinician needs to know about evidence-based anticoagulation in pregnancy

Pregnancy is a hemostatic challenge: women are prone to thromboembolism during their pregnancy and at the same time, especially during delivery, there is substantial risk of bleeding. Pregnant women are often excluded from randomized controlled trials, and high quality evidence regarding optimal anticoagulant management is thus lacking. Anticoagulants are being used in pregnancy for prevention and treatment of various pregnancy complications such as thrombotic events, preeclampsia and pregnancy loss. When anticoagulant therapy is necessary, special attention should be given to both woman and unborn child. In this review, we aim to 1) provide an overview of safe anticoagulant use in pregnancy, 2) discuss treatment goals in pregnancy, and 3) summarize the evidence available to guide decision making for frequently encountered clinical dilemmas in this field

Sex matters: Practice 5P's when treating young women with venous thromboembolism

Sex matters when it comes to venous thromboembolism (VTE). We defined 5P's – period, pill, prognosis, pregnancy, and postthrombotic syndrome – that should be discussed with young women with VTE. Menstrual blood loss (Period) can be aggravated by anticoagulant therapy. This seems particularly true for direct oral anticoagulants. Abnormal uterine bleeding can be managed by hormonal therapy, tranexamic acid, or modification of treatment. The use of combined oral contraceptives (Pill) is a risk factor for VTE. The magnitude of the risk depends on progestagen types and estrogen doses used. In women using therapeutic anticoagulation, concomitant hormonal therapy does not increase the risk of recurrent VTE. Levonorgestrel-releasing intrauterine devices and low-dose progestin-only pills do not increase the risk of VTE. In young women VTE is often provoked by transient hormonal risk factors that affects prognosis. Sex is incorporated as predictor in recurrent VTE risk assessment models. However, current guidelines do not propose using these to guide treatment duration. Pregnancy increases the risk of VTE by 4-fold to 5-fold. Thrombophilia and obstetric risk factors further increase the risk of pregnancy-related VTE. In women with a history of VTE, the risk of recurrence during pregnancy or post partum appears to be influenced by risk factors present during the first VTE. In most women with a history of VTE, antepartum and postpartum thromboprophylaxis with low-molecular-weight heparin is indicated. Women generally are affected by VTE at a younger age then men, and they have to deal with long-term complications (Post-thrombotic syndrome) of deep vein thrombosis early in life

Effect of polypharmacy on bleeding with rivaroxaban versus vitamin K antagonist for treatment of venous thromboembolism

Background Polypharmacy, including use of inhibitors of CYP3A4 and P-glycoprotein (P-gp), is common in patients with venous thromboembolism (VTE) and is associated with increased bleeding. Methods In 8246 patients included in the EINSTEIN-VTE studies for acute VTE, we evaluated the effect of polypharmacy on bleeding and on the relative differences between rivaroxaban and enoxaparin/vitamin K antagonist (VKA). We assessed the incidence of clinically relevant bleeding (major and clinically relevant nonmajor bleeding) by number of comedications (none, 1-3, >= 4) at baseline, and by use of CYP3A4 and/or P-gp inhibitors. Interaction between rivaroxaban versus enoxaparin/VKA and comedication was assessed by Cox regression analysis with p(interaction) estimates. Results With increasing number of comedications, the incidence of clinically relevant bleeding rose from 5.7% to 13.3% in rivaroxaban recipients and from 9.1% to 11.1% in enoxaparin/VKA recipients. Whereas rivaroxaban was associated with a reduced bleeding risk compared with enoxaparin/VKA in patients without comedication (hazard ratio [HR] 0.6, 95% confidence interval [CI] 0.4-0.9), the risk was similar in patients with >= 4 comedications (HR 1.2, 95% CI 0.97-1.5, p(interaction) .002). Use of CYP3A4 and/or P-gp inhibitors was associated with a doubled bleeding risk compared with no use, without a difference between rivaroxaban and enoxaparin/VKA. Conclusion We conclude that fixed-dose rivaroxaban as compared with enoxaparin followed by dose-adjusted VKA is not associated with an increased bleeding risk in patients with VTE administered polypharmacy in general and CYP3A4 and/or P-gp inhibitors specifically. This implies that the observed increased bleeding risks with polypharmacy and use of CYP3A4 and/or P-gp inhibitors are likely explained by comorbidities and frailty, and not by pharmacokinetic interactions

Pregnancy in women with an inferior vena cava filter: A tertiary center experience and overview of the literature

Patients with an inferior vena cava (IVC) filter that remains in situ encounter a lifelong increased risk of deep vein thrombosis and IVC filter complications including fracture, perforation, and IVC filter thrombotic occlusion. Data on the safety of becoming pregnant with an in situ IVC filter are scarce. The objective was to evaluate the risk of complications of in situ IVC filters during pregnancy. We performed a retrospective cohort study of pregnant patients with an in situ IVC filter from a tertiary center between 2000 and 2020. We collected data on complications of IVC filters and pregnancy outcomes. Additionally, we performed a systematic literature search in MEDLINE, Embase, and gray literature. We identified 7 pregnancies in 4 patients with in situ IVC filters with a mean time since IVC filter insertion of 3 years (range, 1-8). No complications of IVC filter occurred during pregnancy. Review of literature yielded five studies including 13 pregnancies in 9 patients. In 1 pregnancy a pre-existent, until then asymptomatic, chronic perforation of the vena cava wall by the IVC filter caused major bleeding and uterine trauma with fetal loss. Overall, the complication rate was 5%. It seems safe to become pregnant with an indwelling IVC filter that is intact and does not show signs of perforation, but because of the low number of cases, no firm conclusions about safety of in situ IVC filters during pregnancy can be drawn. We suggest imaging before pregnancy to reveal asymptomatic IVC filter complications

Effect of polypharmacy on bleeding with rivaroxaban versus vitamin K antagonist for treatment of venous thromboembolism

Background: Polypharmacy, including use of inhibitors of CYP3A4 and P-glycoprotein (P-gp), is common in patients with venous thromboembolism (VTE) and is associated with increased bleeding. Methods: In 8246 patients included in the EINSTEIN-VTE studies for acute VTE, we evaluated the effect of polypharmacy on bleeding and on the relative differences between rivaroxaban and enoxaparin/vitamin K antagonist (VKA). We assessed the incidence of clinically relevant bleeding (major and clinically relevant nonmajor bleeding) by number of comedications (none, 1–3, ≥4) at baseline, and by use of CYP3A4 and/or P-gp inhibitors. Interaction between rivaroxaban versus enoxaparin/VKA and comedication was assessed by Cox regression analysis with pinteraction estimates. Results: With increasing number of comedications, the incidence of clinically relevant bleeding rose from 5.7% to 13.3% in rivaroxaban recipients and from 9.1% to 11.1% in enoxaparin/VKA recipients. Whereas rivaroxaban was associated with a reduced bleeding risk compared with enoxaparin/VKA in patients without comedication (hazard ratio [HR] 0.6, 95% confidence interval [CI] 0.4–0.9), the risk was similar in patients with ≥4 comedications (HR 1.2, 95% CI 0.97–1.5, pinteraction.002). Use of CYP3A4 and/or P-gp inhibitors was associated with a doubled bleeding risk compared with no use, without a difference between rivaroxaban and enoxaparin/VKA. Conclusion: We conclude that fixed-dose rivaroxaban as compared with enoxaparin followed by dose-adjusted VKA is not associated with an increased bleeding risk in patients with VTE administered polypharmacy in general and CYP3A4 and/or P-gp inhibitors specifically. This implies that the observed increased bleeding risks with polypharmacy and use of CYP3A4 and/or P-gp inhibitors are likely explained by comorbidities and frailty, and not by pharmacokinetic interactions

Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis

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Lower prevalence of subsegmental pulmonary embolism after application of the YEARS diagnostic algorithm

The rate of identified isolated subsegmental pulmonary embolism (ssPE) has doubled with advances in computed tomography pulmonary angiography (CTPA) technology, but its clinical relevance is debated. The YEARS diagnostic algorithm was shown to safely reduce the number of required CTPAs in the diagnostic management of PE. We hypothesized that the higher threshold for performing CTPA in YEARS was associated with a lower prevalence of ssPE compared to the conventional diagnostic algorithm. We compared 2291 consecutive patients with suspected PE managed according to YEARS to 3306 consecutive control patients managed according to the Wells score for the prevalence of isolated ssPE. In the YEARS cohort, 52% were managed without CTPA, 12% had pulmonary embolism (PE) of which 10% were isolated ssPE, and the 3-month diagnostic failure rate was 0·35%. In the control cohort, 32% were managed without CTPA, 20% had PE of which 16% were isolated ssPE, and the 3-month failure rate was 0·73%. The isolated ssPE prevalence was significantly lower in YEARS (absolute difference 6·2% (95% confidence interval [CI] 1·4–10), Odds Ratio 0·58 (95% CI 0·37–0·90). In conclusion, YEARS is associated with a lower prevalence of isolated ssPE, due to reduction in CTPAs by the higher D-dimer threshold. This was however not associated with a higher risk of recurrent VTE during follow-up

Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis

Thus far, the association between residual vein occlusion and immediate compression therapy and postthrombotic syndrome is undetermined. Therefore, we investigated whether compression therapy immediately after diagnosis of deep vein thrombosis affects the occurrence of residual vein obstruction (RVO), and whether the presence of RVO is associated with postthrombotic syndrome and recurrent venous thromboembolism. In a prespecified substudy within the IDEAL (individualized duration of elastic compression therapy against long-term duration of therapy for prevention of postthrombotic syndrome) deep vein thrombosis (DVT) study, 592 adult patients from 10 academic and nonacademic centers across The Netherlands, with objectively confirmed proximal DVT of the leg, received no compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg). Presence of RVO and recurrent venous thromboembolism was confirmed with compression ultrasonography and incidence of postthrombotic syndrome as a Villalta score of at least 5 at 6 and 24 months. The average time from diagnosis until assessment of RVO was 5.3 (standard deviation, 1.9) months. A significantly lower percentage of patients who did receive compression therapy immediately after DVT had RVO (46.3% vs 66.7%; odds ratio, 0.46; 95% confidence interval, 0.27-0.80; P = .005). Postthrombotic syndrome was less prevalent in patients without RVO (46.0% vs 54.0%; odds ratio, 0.65; 95% confidence interval, 0.46-0.92; P = .013). Recurrent venous thrombosis showed no significant association with RVO. Immediate compression should therefore be offered to all patients with acute DVT of the leg, irrespective of severity of complaints. This study was registered at ClinicalTrials.gov (NCT01429714) and the Dutch Trial registry in November 2010 (NTR2597)