Recurrent venous thromboembolism: what is the risk and how to prevent it.
ABSTRACT: Venous thromboembolism (VTE) that includes deep vein thrombosis and/or pulmonary embolism is a frequent, severe, and potentially lethal disease. After a first episode, VTE has a strong tendency to recur. While VTE is an acute disease, it may have variable outcomes in early and late phases after initial presentation. Furthermore, the incidence of late, clinically important consequences (postthrombotic syndrome and/or chronic thromboembolic pulmonary hypertension) increases in case of recurrent events. The aims of the present review are (i) to analyze the incidence and risk factors for recurrence of VTE (either those related to the type of first thrombotic event or to the patients), the risks associated with occurrence of recurrent events, and the problems linked to the diagnosis, not always easy, of recurrent events; (ii) to discuss whether or not it is possible to predict the individual risk of recurrence after a first event, by stratifying patients at high or low risk of recurrence, and how this can influence their treatment; (iii) to comment what the current guidelines and guidance suggest/recommend about anticoagulant treatment after a first VTE event and, finally, to propose practical indications on how to manage individual patients affected by VTE.
Project description:OBJECTIVES:To determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, and the cumulative incidence for recurrent VTE up to 10 years. DESIGN:Systematic review and meta-analysis. DATA SOURCES:Medline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019). STUDY SELECTION:Randomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment. DATA EXTRACTION AND SYNTHESIS:Two investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity. RESULTS:18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%). CONCLUSIONS:In patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42017056309.
Project description:Patients with chronic thromboembolic pulmonary hypertension (CTEPH) require lifelong anticoagulation therapy. However, the bleeding risk and recurrence of venous thromboembolism (VTE) in CTEPH patients who are administered warfarin have not been adequately evaluated. The purpose of this study was to evaluate the risk of clinically relevant bleeding, recurrent VTE, and clinical worsening in patients with CTEPH who were administered warfarin. The clinical records of 72 patients with CTEPH who regularly visited our institution and were administered warfarin were retrospectively reviewed between 1 January 2011 and 31 December 2015. We investigated the incidence of clinically relevant bleeding events, recurrent VTE, and hospitalization for the deterioration of pulmonary hypertension or right heart failure (RHF) during the observation period. The mean observation period for the 72 patients was 3.60?±?1.60 person-years. Clinically relevant bleeding, RHF, and recurrent VTE occurred in 21 (29.2%), eight (11.1%), and three (4.2%) of 72 patients, respectively, and the incidence rates for these events were 8.1%/person-year, 3.1%/person-year, and 1.2%/person-year, respectively. The incidence rates for the major and non-major bleeding events were 5.0%/person-year and 3.9%/person-year, respectively. The incidence of clinically relevant bleeding events was 20.8%/person-year during medical treatment with a soluble guanylate cyclase stimulator. One of 35 patients (2.9%) during the post-pulmonary endarterectomy period experienced hemoptysis during observation period (> 6 months after pulmonary endarterectomy). No bleeding events occurred during the post-balloon pulmonary angioplasty period. In conclusion, warfarin effectively prevents VTE recurrence in CTEPH patients, but its effects may be associated with a considerable bleeding risk.
Project description: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.
Project description:Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear whether height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women,s Health Study, we explored whether greater height was associated with increased risk of VTE recurrence.Among 1,691 women who experienced an initial VTE event, 286(16.9%) experienced a recurrent event. Risk of recurrence was 76%(95% CI: 16% -186%) higher among women >66 inches [168 cm] tall relative to those ?62 inches [158 cm] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk.
Project description:This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ?3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.
Project description:BACKGROUND:Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. METHODS AND FINDINGS:PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was provoked or unprovoked. When analyzing risk factors among PWH, the main focus of analysis was the role of immune markers (cluster of differentiation 4 [CD4]+ T-cell count). There were 153 PWH (82% men, median 48 years) and 4,005 uninfected controls (45% men, median 49 years) with a first VTE (71% unprovoked in PWH, 34% unprovoked in controls) available for analysis. With 40 VTE recurrences during 774 person-years of follow-up (PYFU) in PWH and 635 VTE recurrences during 20,215 PYFU in controls, the incidence rates were 5.2 and 3.1 per 100 PYFU (HR: 1.70, 95% CI 1.23-2.36, p = 0.003). VTE consistently recurred more frequently per 100 PYFU in PWH in all predefined subgroups of men (5.6 versus 4.8), women (3.6 versus 1.9), and unprovoked (6.0 versus 5.2) or provoked (3.1 versus 2.1) first VTE. After adjustment, the VTE recurrence risk was higher in PWH compared to controls in the first year after anticoagulant discontinuation (HR: 1.67, 95% CI 1.04-2.70, p = 0.03) with higher cumulative incidences in PWH at 1 year (12.5% versus 5.6%) and 5 years (23.4% versus 15.3%) of follow-up. VTE recurred less frequently in PWH who were more immunodeficient at the first VTE, marked by a better CD4+ T-cell recovery on antiretroviral therapy and during anticoagulant therapy for the first VTE (adjusted HR: 0.81 per 100 cells/mm3 increase, 95% CI 0.67-0.97, p = 0.02). Sensitivity analyses addressing potential sources of bias confirmed our principal analyses. The main study limitations are that VTEs were adjudicated differently in the cohorts and that diagnostic practices changed during the 20-year study period. CONCLUSIONS:Overall, the risk of recurrent VTE was elevated in PWH compared to controls. Among PWH, recurrence risk appeared to decrease with greater CD4+ T-cell recovery after a first VTE. This is relevant when deciding to (dis)continue anticoagulant therapy in PWH with otherwise unprovoked first VTE.
Project description:BACKGROUND:In patients with a first, unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulant therapy (AT) is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. The objective of this study is to assess among patients with a first acute pulmonary embolism (PE) who received ?3 months of AT and thereafter had a planar lung scan, whether residual pulmonary vascular obstruction (RPVO) is associated with VTE recurrence after discontinuation of AT. METHODS AND ANALYSIS:We will conduct a systematic review with a meta-analysis of individual participant data of contemporary studies evaluating the prognostic significance of RPVO in patients with a first acute PE. We will search from inception to 24 January 2018, PubMed, Medline, Embase and Cochrane's Central Registry for Randomized Controlled Trials, CENTRAL for randomized controlled trials and prospective cohort studies. Two reviewers will conduct all screening and data collection independently. The methodological quality and risk of bias of eligible studies will be carefully and rigorously assessed using the Risk Of Bias In Non-randomised Studies of Interventions tool. The primary objective will be to assess the relationship between RPVO on ventilation-perfusion scan after completion of at least 3 months of AT after an acute PE event, and the risk of an objectively confirmed symptomatic recurrent VTE (including deep vein thrombosis or PE) or death due to PE. The secondary objectives will include the assessment of the optimal RPVO cut-off and the risk of recurrent VTE, as well as the relationship between the relative change in RPVO between PE diagnosis and at discontinuation of AT (?3 months) and risk of recurrent VTE. ETHICS AND DISSEMINATION:This study of secondary data does not require ethics approval. It will be presented internationally and published in the peer-reviewed literature. PROSPERO REGISTRATION NUMBER:CRD42017081080.
Project description:BACKGROUND:Venous thromboembolism (VTE) is highly prevalent in cancer patients and can cause severe morbidity. VTE treatment is essential, but anticoagulation increases the risk of major bleeding. The purpose was to evaluate the impact of VTE and major bleeding on survival and to identify significant risk factors for these events in lung cancer patients. METHODS:Data were extracted from a permanent sample of the French national health information system (including hospital and out-of-hospital care) from 2009 to 2016. All episodes of VTE and major bleeding events within one year after cancer diagnosis were identified. A Cox model was used to analyse the effect of VTE and major bleeding on the patients' one-year survival. VTE and major bleeding risk factors were analysed with a Fine and Gray survival model. RESULTS:Among the 2553 included patients with lung cancer, 208 (8%) had a VTE episode in the year following diagnosis and 341 (13%) had major bleeding. Almost half of the patients died during follow-up. Fifty-six (60%) of the patients presenting with pulmonary embolism (PE) died, 48 (42%) of the patients presenting with deep vein thrombosis (DVT) alone died and 186 (55%) of those presenting with a major bleeding event died. The risk of death was significantly increased following PE and major bleeding events. VTE concomitant with cancer diagnosis was associated with an increased risk of VTE recurrence beyond 6?months after the first VTE event (sHR?=?4.07 95% CI: 1.57-10.52). Most major bleeding events did not appear to be related to treatment. CONCLUSION:VTE is frequent after a diagnosis of lung cancer, but so are major bleeding events. Both PE and major bleeding are associated with an increased risk of death and could be indicators of lung cancer mortality.
Project description:Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences.
Project description:Previous reports show increased incidence of venous thromboembolism [VTE, deep-vein thrombosis (DVT) and pulmonary embolus (PE)] in sickle cell disease (SCD) patients. The incidence, time course, and risk factors for VTE recurrence have been less well described. We determined the cumulative incidence of first VTE recurrence and bleeding in a cohort of SCD patients with incident VTE. Risk factors for recurrence and bleeding were also determined using multivariable Cox regression models, adjusting for gender, race/ethnicity, era of incident VTE, location and hospitalization-associated status of incident VTE, and SCD-related complications. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Among 877 SCD patients with an incident VTE, the 1-year and 5-year cumulative incidence of recurrence was 13.2% (95% CI 11.0%-15.5%) and 24.1% (95% CI 21.2%-27.1%). Risk factors for VTE recurrence included more severe SCD (HR = 2.41; CI: 1.67-3.47), lower extremity DVT as the incident event (HR = 1.64; CI: 1.17-2.30), and pneumonia/acute chest syndrome (HR = 1.68; CI: 1.15-2.45). The cumulative incidence of bleeding was 4.9% (CI 3.5%-6.4%) at 6 months and 7.9% (CI: 6.2%-9.8%) at 1 year. More severe SCD (HR = 1.61; CI: 1.11-2.35) was associated with bleeding. The high incidence of VTE recurrence in patients with SCD suggests that extended anticoagulation may be indicated; however, this must be weighed against a relatively high risk of bleeding. Prospective, randomized studies of anticoagulation in SCD patients with VTE are needed.