Treatment of venous thromboembolism during pregnancy

BackgroundAcute VTE occurs with an incidence of 1–2/1,000 during pregnancy and is associated with an acute mortality of 1–2%. However, data on VTE treatment during pregnancy are sparse: Even though 50 cases occur daily in the EU and US, a recent review identified only 174 cases in the literature.Acute treatmentStandard treatment is LMWH at therapeutic doses or APTT-adjusted UFH. LMWH is at least as safe and effective as UFH in non-pregnant patients. In pregnancy, LMWH is the preferred option, because it offers better bioavailability, fewer injections, superior safety regarding HIT and osteoporosis.Long-term treatmentVKA are contraindicated because of teratogenicity and thus heparin is used for secondary prevention. Since UFH requires therapeutic doses throughout pregnancy, carrying the risk of osteoporosis, LMWH is the drug of choice. In a recent review most patients were treated initially with LMWH, predominately with twice daily injections. Recurrent VTE occurred in 1.2%, bleeding in 1.7%, with no HIT. Whether the long-term dose of LMWH can be reduced remains unresolved: Intermediate dose LMWH has been used effectively in cancer patients, who — like pregnant women — continue to have a high pro-thrombotic burden after the initial phase.ConclusionEven though acute VTE is not uncommon and represents a life-threatening event during pregnancy, data are sparse, and prospective trial data are needed to answer open questions concerning treatment modalities. Nevertheless, it is evident that LMWH is the preferred option for treatment of VTE during pregnancy.     

Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium

Venous thromboembolism is a rare but threatening complication of pregnancy. Little conclusive information is available on the actual risk of venous thromboembolism during pregnancy or puerperium in women with inherited thrombophilia, particularly in carriers of factor V Leiden and of the G20210A prothrombin gene mutation. To determine the pregnancy-related and puerperium-related risk of venous thromboembolism in women with inherited thrombophilia, we performed a case-control study on 119 women who had a first episode of deep vein thrombosis and/or pulmonary embolism during pregnancy or puerperium and 232 healthy women who had at least one pregnancy without thrombosis. Inherited thrombophilia was diagnosed in 47 patients (39.5%) and 15 controls (6.5%). The relative risk of venous thromboembolism was 10.6 (95% CI, 5.6-20.4) for heterozygous carriers of factor V Leiden, 2.9 (95% CI, 1.0-8.6) for heterozygous carriers of the prothrombin mutation and 13.1 (95% CI, 5.0-34.2) for those with antithrombin, protein C or protein S deficiency taken together. Sixty-eight of the 119 women (57%) had thrombosis after delivery, confirming the puerperium as a particularly high-risk period. When women were divided into two groups of those with antenatal or postnatal thrombosis. the relative risks associated with each type of inherited thrombophilia were of similar magnitude. In conclusion, women with inherited thrombophilia have an increased risk of venous thromboembolism during pregnancy. Among thrombophilic abnormalities, the prothrombin mutation was the weakest risk factor. Thrombosis occurred more frequently in puerperium than in pregnancy, whether or not thrombophilia was diagnosed.     

The incidence and risk factors of recurrent venous thromboembolism during pregnancy

Introduction

Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode.

Materials and Methods

This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis).

Results and Conclusions

The incidence of recurrent VTE was 7.6% (n = 28).Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis.In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p < 0.001; group A vs. C: 5.7% vs. 30.0%, p = 0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p = 0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p = 0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p < 0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.     

Treatment of venous thromboembolism

The combination of heparin and oral anticoagulants has been the treatment of choice for most patients with venous thromboembolism in the last two decades. Heparin has been proven to be effective when administered by intravenous continuous infusion or by subcutaneous injection. Oral anticoagulants should be started at the same time and heparin should be discontinued when the levels of the International Normalized Ratio reach the therapeutic range, between 2.0 and 3.0. Low molecular weight heparin has potential advantages over heparin and can be administered in subcutaneous weight-adjusted fixed doses without need for monitoring. This has made home treatment of a large proportion of patients possible. Randomized clinical trials have demonstrated the efficacy and safety of this approach. The optimal duration of the secondary prophylaxis with oral anticoagulants is still a matter of debate. The rate of recurrence has been shown to be elevated, particularly in those patients with idiopathic venous thromboembolism. The presence of an active cancer or a thrombophilic state may require long-term anticoagulation, although not all the congenital hypercoagulable states seem to carry the same level of risk. A 3-month therapy is recommended when a transient risk factor is identified; lifelong treatment is recommended for patients with a second episode of venous thromboembolism. In all other cases, 6 months are currently recommended, but thereafter close monitoring of the patients is advisable. The use of different treatment strategies such as vena caval filter placement, thrombolysis, and surgical thrombectomy should be restricted to a limited number of situations.     

The diagnostic management of acute venous thromboembolism during pregnancy: recent advancements and unresolved issues

Adequate diagnostic management of suspected venous thromboembolism (VTE) in pregnant women is of great importance. The diagnostic performance of clinical decision rules and D-dimer testing is influenced by physiological changes during pregnancy and is understudied. Recent studies have addressed these issues by developing a new clinical decision rule and raising the D-dimer level cut-off points. With imaging of suspected pulmonary embolism (PE) the radiation exposure remains a concern. Recent studies have adjusted CT settings and scan length to minimize this exposure without loss of image quality. Furthermore the first choice imaging modality of suspected PE in pregnant women remains a matter of debate in view of studies showing high inadequacy rates for both CT scanning and VQ scanning. Issues concerning the diagnostic management of VTE in pregnant women and advancements made in recent years will be discussed.     

Cost-effectiveness of low-molecular-weight heparin for secondary prophylaxis of cancer-related venous thromboembolism

Although extended secondary prophylaxis with low-molecular-weight heparin was recently shown to be more effective than warfarin for cancer-related venous thromboembolism, its cost-effectiveness compared to traditional prophylaxis with warfarin is uncertain. We built a decision analytic model to evaluate the clinical and economic outcomes of a 6-month course of low-molecular-weight heparin or warfarin therapy in 65-year-old patients with cancer-related venous thromboembolism. We used probability estimates and utilities reported in the literature and published cost data. Using a US societal perspective, we compared strategies based on quality-adjusted life-years (QALYs) and lifetime costs. The incremental cost-effectiveness ratio of low-molecular-weight heparin compared with warfarin was 149,865 dollars/QALY. Low-molecular-weight heparin yielded a quality-adjusted life expectancy of 1.097 QALYs at the cost of 15,329 dollars. Overall, 46% (7108 dollars) of the total costs associated with low-molecular-weight heparin were attributable to pharmacy costs. Although the low-molecular-weigh heparin strategy achieved a higher incremental quality-adjusted life expectancy than the warfarin strategy (difference of 0.051 QALYs), this clinical benefit was offset by a substantial cost increment of 7,609 dollars. Cost-effectiveness results were sensitive to variation of the early mortality risks associated with low-molecular-weight heparin and warfarin and the pharmacy costs for low-molecular-weight heparin. Based on the best available evidence, secondary prophylaxis with low-molecular-weight heparin is more effective than warfarin for cancer-related venous thromboembolism. However, because of the substantial pharmacy costs of extended low-molecular-weight heparin prophylaxis in the US, this treatment is relatively expensive compared with warfarin.     

Treatment of venous thromboembolism in cancer patients

The management of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with cancer can be a clinical dilemma. Comorbid conditions, warfarin failure, difficult venous access, and a high bleeding risk are some of the factors that often complicate anticoagulant therapy in these patients. In addition, the use of central venous access devices is increasing but the optimal treatment of catheter-related thrombosis remains controversial. Unfractionated heparin (UFH) is the traditional standard for the initial treatment of venous thromboembolism (VTE) but low molecular weight heparins (LMWHs) have been shown to be equally safe and effective in hemodynamically stable patients. For long-term treatment or secondary prophylaxis, vitamin K antagonists remain the mainstay treatment. However, the inconvenience and narrow therapeutic window of oral anticoagulants make extended therapy unattractive and problematic. As a result, LMWHs are being evaluated as an alternative for long-term therapy. New antithrombotic agents are being tested in clinical trials and may have the potential to replace conventional treatment. The role of inferior vena cava filters in cancer patients remains ill defined but these devices remain the treatment of choice in patients with contraindications for anticoagulant therapy.     

Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women

Women with a history of venous thromboembolism (VTE), thrombophilia or both may be at increased risk of thrombosis during pregnancy, but the optimal management strategy is not well defined in clinical guidelines because of limited trial data. A strategy of risk assessment and heparin prophylaxis was evaluated in pregnant women at increased risk of VTE. In a prospective trial (Efficacy of Thromboprophylaxis as an Intervention during. Gravidity [EThIG]), 810 pregnant women were assigned to one of three management strategies according to pre-defined risk factors related to history of VTE and thrombophilic profile. Low-risk women (group I), received 50-100 IU dalteparin/kg body weight/day for 14 days postpartum, or earlier when additional risk factors occurred. Women at high (group II) or very high risk (group III) received dalteparin from enrollment until six weeks postpartum (50-100 IU and 100-200 IU/kg/day, respectively). Objectively confirmed, symptomatic VTE occurred in 5/810 women (0.6%; 95% confidence interval [CI], 0.2 to 1.5%) (group I, 0 of 225; II, 3/469; III, 2/116). The rate of serious bleeding was 3.0% (95 % CI, 1.9 to 4.4%); 1.1% (95 % CI, 0.5 to 2.2%) was possibly dalteparin-related. There was no evidence of heparin-induced thrombocytopenia, one case of osteoporosis, and rates of miscarriage and stillbirth were similar to previous, retrospective studies. Risk-stratified heparin prophylaxis was associated with a low incidence of symptomaticVTE and few clinically important adverse events. Antepartum heparin prophylaxis is, therefore, warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia.     

Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy

Low-molecular-weight (LMW) heparins have been shown to be at least as effective as unfractionated (UF) heparin in the treatment of deep venous thrombosis (DVT) in nonpregnant subjects. LMW heparins have been shown to be safe when used during pregnancy as they do not cross the placenta. Up to now, they have been used mainly in thromboprophylaxis during pregnancy and rarely in the treatment of acute DVT in pregnant women. In a prospective observational study, we compared the effectiveness and safety of the LMW heparin, dalteparin, with UF heparin in the initial treatment (first week) of DVT during pregnancy. After confirmation of DVT by ultrasonography, 10 women were treated with UF heparin (25,430 IU/day, mean) and 21 women with dalteparin (16,000 IU/day, mean) for 7 days and, thereafter, all women were given treatment doses of LMW heparin for another 2 weeks. The dose was then gradually decreased and kept at a high prophylactic dose until delivery. One patient in the dalteparin group had recurrence of DVT 2 weeks after starting the treatment. No differences were observed between the groups in symptoms or bleeding complications during pregnancy and delivery. Our results indicate that LMW heparin is as effective and safe as UF heparin for the first week of treatment, but LMW heparin has the advantage of being easily administered and few laboratory controls are required.     

Sustained impact of electronic alerts on rate of prophylaxis against venous thromboembolism

Advanced electronic alerts (eAlerts) and computerised physician order entry (CPOE) increase adequate thromboprophylaxis orders among hospitalised medical patients. It remains unclear whether eAlerts maintain their efficacy over time, after withdrawal of continuing medical education (CME) on eAlerts and on thromboprophylaxis indications from the study staff. We analysed 5,317 hospital cases from the University Hospital Zurich during 2006-2009: 1,854 cases from a medical ward with eAlerts (interventiongroup) and 3,463 cases from a surgical ward without eAlerts (controlgroup). In the intervention group, an eAlert with hospital-specific venous thromboembolism (VTE) prevention guidelines was issued in the electronic patient chart 6 hours after admission if no pharmacological or mechanical thromboprophylaxis had been ordered. Data were analysed for three phases: pre-implementation (phase 1), eAlert implementation with CME (phase 2), and post-implementation without CME (phase3). The rates of thromboprophylaxis in the intervention group were 43.4% in phase 1 and 66.7% in phase 2 (p<0.001), and increased further to 73.6% in phase3 (p=0.011). Early thromboprophylaxis orders within 12 hours after admission were more often placed in phase 2 and 3 as compared to phase 1 (67.1% vs. 52.1%, p<0.001). In the surgical control group, the thromboprophylaxis rates in the three phases were 88.6%, 90.7%, 90.6% (p=0.16). Advanced eAlerts may provide sustained efficacy over time, with stable rates of thromboprophylaxis orders among hospitalised medical patients.     

CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency

Patients with severe renal insufficiency (sRI) have been suggested to be at an increased risk of bleeding with low-molecular-weight heparins (LMWH). We aimed at assessing the benefits and risks of certoparin in comparison to unfractionated heparin (UFH) in these patients. In this subgroup analysis of the CERTIFY trial, acutely ill, non-surgical patients ≥70 years received certoparin 3,000U aXa o.d. or UFH 5,000 IU t.i.d. One hundred eighty-nine patients had a glomerular filtration rate (GFR) ≤30 ml/min/1.73 m2, 3,050 patients served as controls. Patients with sRI had a mean age of 85.9 ± 6.6 years (controls 78.4 ± 6.0) and were treated for a mean of 9.3 ± 3.7 days (9.9 ± 4.3). Thromboembolic event rates were comparable (4.55 vs. 4.21%; OR1.08; 95%CI 0.5-2.37) but bleeding was increased in sRI (9.52 vs. 3.54%; OR2.87; 95%CI 1.70-4.83). The incidence of the combined end-point of proximal DVT, symptomatic non-fatal PE and VTE related death was 6.49% with certoparin and 2.60% with UFH (OR2.60; 95%CI 0.49-13.85). There was a decrease in total bleeding with certoparin (OR0.33; 95%CI 0.11-0.97), which was non-significant in patients with GFR >30 ml/min/1.73 m2. In two multivariable regression models certoparin and immobilisation <10 days were associated with less bleeding while a GFR ≤30 ml/min/1.73 m2 was associated with increased bleeding. A total of 11.3% of certoparin- and 18.5% of UFH-treated patients experienced serious adverse events (14.8 in patients with a GFR ≤30 vs. 5.6% vs. >30 ml/min/1.73 m2). In conclusion, certoparin 3,000U anti Xa o.d. was as efficacious as 5,000 IU UFH t.i.d. in patients with sRI but had a reduced risk of bleeding.     

Preeclampsia and pregnancy loss in women with a history of venous thromboembolism and prophylactic low-molecular-weight heparin (LMWH) during pregnancy

Limited data are available regarding complications of pregnancy and pregnancy outcome under prophylaxis with low-molecular-weight heparin (LMWH) in women with a history of thromboembolism (TE). We retrospectively evaluated pregnancy complications in a cohort of 80 women. All had a history of TE (76 venous, two arterial and two venous and arterial) and received prophylactic LMWH during 86 pregnancies. The rate of preeclampsia and stillbirth in these women was compared to that of a control group of 313 women without a history of TE and LMWH. Prophylaxis was started at a median of 10 weeks of gestation and usually continued until six weeks post partum. In 94% of the cases the outcome of pregnancy was favourable with a live birth. Four pregnancies (4.7%) ended in miscarriage. Two (2.3%) pregnancies were complicated by a thromboembolic event (one deep leg vein thrombosis and PRIND, respectively). One patient developed HELLP-syndrome. Severe preeclampsia occurred in three (3.8%) and stillbirth in one (1.3%) of the patients (n = 80), whereas this was the case in four (1.3%, odds ratio 3.01; 95% confidence interval (CI) 0.66-13.73, p = 0.15) and 10 (3.2%, OR = 0.38; 95% CI 0.05-3.04, p = 0.72) control women. Mean birth weight and standard deviation of infants was 3,160 +/- 930 g in patients and 3,300 +/- 540 g in controls (p = 0.11). We conclude that a favourable pregnancy outcome in women with a history of thromboembolism who use prophylactic LMWH during pregnancy can be expected. There was a trend towards a higher risk of preeclampsia, and these women should be carefully monitored for this complication.     

Risk-assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease

Introduction

There is a lack of evidence regarding the need for thromboprophylaxis in hospitalized patients with liver disease. The purpose of this study was to evaluate the Padua Predictor Score (PPS) as a risk-stratification tool for the development of venous thromboembolism (VTE) in patients with chronic liver disease.

Methods

This was a retrospective cohort study conducted in an academic medical center in the United States. Consecutive adult patients admitted with chronic liver disease were included. Patients were categorized into two groups based on whether they developed a VTE or not. The risk for VTE in each patient was evaluated using the Padua Predictor Score (PPS). Patients were risk stratified using the PPS score as high-risk (score ≥ 4) and low-risk (score < 4). The risk of VTE based on PPS categorization was evaluated using logistic regression.

Results

A total of 163 patients with liver disease were included in the study cohort. Of these, 18 (11%) developed VTE. Mean PPS was significantly greater in the VTE group than the non-VTE group (5.8 ± 2.0 versus 3.0 ± 2.1, respectively; p < 0.001). In high-risk patients 22% (n = 16/72) developed VTE and in low-risk patients 2% (2/91) developed VTE (p < 0.001). High-risk patients were more likely to have VTE (OR 12.7, 95% CI 2.8 to 57.4, p = 0.001).

Conclusion

The PPS is an effective risk assessment tool for VTE in patients hospitalized with chronic liver disease.     

Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy

Increased thromboembolic events occur in women with mechanical prosthetic valves during pregnancy, and selecting an effective and safe anticoagulant is still a challenge. Low molecular weight heparin (LMWH) is a promising alternative, but a recent warning and label change about its use in patients with mechanical prosthetic valves has caused confusion among physicians. The aim of the present study was to review the risks of maternal and fetal complications with mechanical heart valves treated with LMWH during pregnancy. We performed a review of the current medical literature through MEDLINE and EMBASE (1989 to 2004). Additional data sources included abstract proceedings, and reference lists of selected articles. Among 81 pregnancies in 75 women, the proportion of valve thrombosis was 8.64% (7/81; 95% CI, 2.52%-14.76%). The frequency of overall thromboembolic complication (TEC) was 12.35% (10/81; 95% CI, 5.19%-19.51%). Nine of ten patients with TEC received a fixed dose of LMWH and two of these received a fixed low dose of LMWH. Among 51 pregnancies whose anti-factor Xa levels were monitored, only one patient was reported to have a thromboembolic complication. The frequency of live births with LMWH was 87.65% (95%CI, 80.49%-94.81%). In pregnant women with mechanical heart valves, LMWH appears to be a suitable option to a vitamin K antagonist. The use of LMWH warrants monitoring and appropriate dose adjustments to maintain a 4-6 hr post-injection anti-factor Xa level at a minimum of 1.0 U/ml to decrease the incidence of TEC.