Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement†

OBJECTIVES Valve-sparing root replacement (VSRR) is thought to reduce the rate of thromboembolic and bleeding events compared with aortic root replacement using a mechanical aortic root replacement (MRR) with a composite graft by avoiding oral anticoagulation. But as VSRR carries a certain risk for subsequent reinterventions, decision-making in the individual patient can be challenging. METHODS Of 100 Marfan syndrome (MFS) patients who underwent 169 aortic surgeries and were followed at our institution since 1995, 59 consecutive patients without a history of dissection or prior aortic surgery underwent elective VSRR or MRR and were retrospectively analysed. RESULTS VSRR was performed in 29 (David n = 24, Yacoub n = 5) and MRR in 30 patients. The mean age was 33 ± 15 years. The mean follow-up after VSRR was 6.5 ± 4 years (180 patient-years) compared with 8.8 ± 9 years (274 patient-years) after MRR. Reoperation rates after root remodelling (Yacoub) were significantly higher than after the reimplantation (David) procedure (60 vs 4.2%, P = 0.01). The need for reinterventions after the reimplantation procedure (0.8% per patient-year) was not significantly higher than after MRR (P = 0.44) but follow-up after VSRR was significantly shorter (P = 0.03). There was neither significant morbidity nor mortality associated with root reoperations. There were no neurological events after VSRR compared with four stroke/intracranial bleeding events in the MRR group (log-rank, P = 0.11), translating into an event rate of 1.46% per patient-year following MRR. CONCLUSION The calculated annual failure rate after VSRR using the reimplantation technique was lower than the annual risk for thromboembolic or bleeding events. Since the perioperative risk of reinterventions following VSRR is low, patients might benefit from VSRR even if redo surgery may become necessary during follow-up.

How to avoid venous thromboembolism in women at increased risk--with special focus on low-risk periods

Venous thromboembolism (VTE) is a major cause of mortality during Western women's fertile life. Although half of thromboembolic events occur during times of low-risk situations, almost all our knowledge is focused on medical thromboprophylaxis during high-risk situations. Thus, since we only use medical thromboprophylaxis at high-risk periods, lifestyle advice could be an attractive complement both during high- and low-risk situations. The knowledge of how lifestyle factors affect VTE risk has grown in recent years, and women at high risk are often highly motivated to make changes in order to reduce their risk. This review is focused on modifiable risk factors for VTE and advice that may be given to women at increased risk of VTE.

Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation.

BACKGROUND Increasing evidence suggests that psychosocial factors, including depression predict incident venous thromboembolism (VTE) against a background of genetic and acquired risk factors. The role of psychosocial factors for the risk of recurrent VTE has not previously been examined. We hypothesized that depressive symptoms in patients with prior VTE are associated with an increased risk of recurrent VTE. METHODS In this longitudinal observational study, we investigated 271 consecutive patients, aged 18 years or older, referred for thrombophilia investigation with an objectively diagnosed episode of VTE. Patients completed the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). During the observation period, they were contacted by phone and information on recurrent VTE, anticoagulation therapy, and thromboprophylaxis in risk situations was collected. RESULTS Clinically relevant depressive symptoms (HADS-D score ≥ 8) were present in 10% of patients. During a median observation period of 13 months (range 5-48), 27 (10%) patients experienced recurrent VTE. After controlling for sociodemographic and clinical factors, a 3-point increase on the HADS-D score was associated with a 44% greater risk of recurrent VTE (OR 1.44, 95% CI 1.02, 2.06). Compared to patients with lower levels of depressive symptoms (HADS-D score: range 0-2), those with higher levels (HADS-D score: range 3-16) had a 4.1-times greater risk of recurrent VTE (OR 4.07, 95% CI 1.55, 10.66). CONCLUSIONS The findings suggest that depressive symptoms might contribute to an increased risk of recurrent VTE independent of other prognostic factors. An increased risk might already be present at subclinical levels of depressive symptoms.

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.

Primary prophylaxis for venous thromboembolism in patients undergoing cardiac or thoracic surgery.

BACKGROUND Cardiac and thoracic surgery are associated with an increased risk of venous thromboembolism (VTE). The safety and efficacy of primary thromboprophylaxis in patients undergoing these types of surgery is uncertain. OBJECTIVES To assess the effects of primary thromboprophylaxis on the incidence of symptomatic VTE and major bleeding in patients undergoing cardiac or thoracic surgery. SEARCH METHODS The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). The authors searched the reference lists of relevant studies, conference proceedings, and clinical trial registries. SELECTION CRITERIA Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). AUTHORS' CONCLUSIONS The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.

Anticoagulation Management Practices and Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Clinical Research Study.

Whether anticoagulation management practices are associated with improved outcomes in elderly patients with acute venous thromboembolism (VTE) is uncertain. Thus, we aimed to examine whether practices recommended by the American College of Chest Physicians guidelines are associated with outcomes in elderly patients with VTE. We studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study and assessed the adherence to four management practices: parenteral anticoagulation ≥5 days, INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulation, early start with vitamin K antagonists (VKA) ≤24 hours of VTE diagnosis, and the use of low-molecular-weight heparin (LMWH) or fondaparinux. The outcomes were all-cause mortality, VTE recurrence, and major bleeding at 6 months, and the length of hospital stay (LOS). We used Cox regression and lognormal survival models, adjusting for patient characteristics. Overall, 9% of patients died, 3% had VTE recurrence, and 7% major bleeding. Early start with VKA was associated with a lower risk of major bleeding (adjusted hazard ratio 0.37, 95% CI 0.20-0.71). Early start with VKA (adjusted time ratio [TR] 0.77, 95% CI 0.69-0.86) and use of LMWH/fondaparinux (adjusted TR 0.87, 95% CI 0.78-0.97) were associated with a shorter LOS. An INR ≥2.0 for ≥24 hours before stopping parenteral anticoagulants was associated with a longer LOS (adjusted TR 1.2, 95% CI 1.08-1.33). In elderly patients with VTE, the adherence to recommended anticoagulation management practices showed mixed results. In conclusion, only early start with VKA and use of parenteral LMWH/fondaparinux were associated with better outcomes.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. PATIENTS Elderly participants with VTE. METHODS In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid stimulating hormone levels (TSH=4.50-19.99 mIU/l), and subclinical hyperthyroidism (SHyper) as TSH<0.45, both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. rVTE incidence rate was 7.2 (95% confidence interval:2.7-19.2) per 100 patient-years in SHypo, 0.0 (0.0-7.6) in SHyper and 5.9 (4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio [SHR] for rVTE was 0.00 (0.00-0.58) in SHyper and 1.50 (0.52-4.34) in SHypo compared to euthyroids, without increased thrombophilic biomarkers. SHyper (HR 0.80,0.23-2.81) and SHypo (HR 0.99,0.30-3.29) were not associated with mortality. CONCLUSION In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers. This article is protected by copyright. All rights reserved.

The Role of Platelets in Venous Thromboembolism

Multiple factors contribute to the risk of venous thromboembolism (VTE). Platelets have attracted much interest in arterial cardiovascular disease, whereas their role in VTE has received much less attention. Recent evidence suggests that platelets may play a more important role in VTE than previously anticipated. This review discusses the mechanisms that link platelets with venous thrombotic disease and their potential applications as novel risk factors for VTE. In addition, animal studies and randomized clinical trials that highlight the potential effect of antiplatelet therapy in venous thrombosis are evaluated to assess the role of platelets in VTE. The clinical significance of platelets for VTE risk assessment in specific patient cohorts and their role as a suitable therapeutic target for VTE prevention is acknowledged. The role of platelets in VTE is a promising field for future research.

Venous thromboembolism in patients with acute leukemia: Prevalence, incidence, recurrence of thrombosis, risk factors, and impact on survival

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most preventable cardiovascular disease and a growing public health problem in the United States. The incidence of VTE remains high with an annual estimate of more than 600,000 symptomatic events. DVT affects an estimated 2 million American each year with a death toll of 300,000 persons per year from DVT-related PE. Leukemia patients are at high risk for both hemorrhage and thrombosis; however, little is known about thrombosis among acute leukemia patients. The ultimate goal of this dissertation was to obtain deep understanding of thrombotic issue among acute leukemia patients. The dissertation was presented in a format of three papers. First paper mainly looked at distribution and risk factors associated with development of VTE among patients with acute leukemia prior to leukemia treatment. Second paper looked at incidence, risk factors, and impact of VTE on survival of patients with acute lymphoblastic leukemia during treatment. Third paper looked at recurrence and risk factors for VTE recurrence among acute leukemia patients with an initial episode of VTE. Descriptive statistics, Chi-squared or Fisher's exact test, median test, Mann-Whitney test, logistic regression analysis, Nonparametric Estimation Kaplan-Meier with a log-rank test or Cox model were used when appropriate. Results from analyses indicated that acute leukemia patients had a high prevalence, incidence, and recurrent rate of VTE. Prior history of VTE, obesity, older age, low platelet account, presence of Philadelphia positive ALL, use of oral contraceptives or hormone replacement therapy, presence of malignancies, and co-morbidities may place leukemia patients at an increased risk for VTE development or recurrence. Interestingly, development of VTE was not associated with a higher risk of death among hospitalized acute leukemia patients.^