Florian Posch

Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants

INTRODUCTION Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE. METHODS A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model. RESULTS LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies. CONCLUSION The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable. FUNDING Austrian Science Fund (FWF-SFB-54).

Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality

In studies on cancer‐associated venous thromboembolism (VTE), patients not only are at risk for VTE but also may die from their underlying malignancy.

Red Cell Distribution Width and Other Red Blood Cell Parameters in Patients with Cancer: Association with Risk of Venous Thromboembolism and Mortality

Background Cancer patients are at high risk of developing venous thromboembolism (VTE). Red cell distribution width (RDW) has been reported to be associated with arterial and venous thrombosis and mortality in several diseases. Here, we analyzed the association between RDW and other red blood cell (RBC) parameters with risk of VTE and mortality in patients with cancer. Methods RBC parameters were measured in 1840 patients with cancers of the brain, breast, lung, stomach, colon, pancreas, prostate, kidney; lymphoma, multiple myeloma and other tumor sites, that were included in the Vienna Cancer and Thrombosis Study (CATS), which is an ongoing prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Primary study outcome is occurrence of symptomatic VTE and secondary outcome is death during a maximum follow-up of 2 years. Results During a median follow-up of 706 days, 131 (7.1%) patients developed VTE and 702 (38.2%) died. High RDW (>16%) was not associated with a higher risk of VTE in the total study cohort; in competing risk analysis accounting for death as competing variable the univariable subhazard ratio (SHR) was 1.34 (95% confidence interval [CI]: 0.80–2.23, p = 0.269). There was also no significant association between other RBC parameters and risk of VTE. High RDW was associated with an increased risk of mortality in the total study population (hazard ratio [HR, 95% CI]: 1.72 [1.39–2.12], p<0.001), and this association prevailed after adjustment for age, sex, hemoglobin, leukocyte and platelet count (HR [95% CI]: 1.34 [1.06–1.70], p = 0.016). Conclusions RDW and other RBC parameters were not independently associated with risk of VTE in patients with cancer and might therefore not be of added value for estimating risk of VTE in patients with cancer. We could confirm that high RDW is an independent predictor of poor overall survival in cancer.

Podoplanin expression in primary brain tumors induces platelet aggregation and increases risk of venous thromboembolism

Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P < .001) and higher D-dimer levels (P < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; P =010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.

Hypercoagulabilty, venous thromboembolism, and death in patients with cancer

Venous thromboembolism (VTE) is a frequent complication of malignancy. The aim of this study was to investigate whether multi-state modelling may be a useful quantitative approach to dissect the complex epidemiological relationship between hypercoagulability, VTE, and death in cancer patients. We implemented a three-state/three-transition unidirectional illness-death model of cancer-associated VTE in data of 1,685 cancer patients included in a prospective cohort study, the Vienna Cancer and Thrombosis Study (CATS). During the two-year follow-up period, 145 (8.6 %) patients developed VTE, 79 (54.5 %) died after developing VTE, and 647 (38.4 %) died without developing VTE, respectively. VTE events during follow-up were associated with a three-fold increase in the risk of death (Transition Hazard ratio (HR)=2.98, 95 % confidence interval [CI]: 2.36-3.77, p< 0.001). This observation was independent of cancer stage. VTE events that occurred later during follow-up exerted a stronger impact on the risk of death than VTE events that occurred at earlier time points (HR for VTE occurrence one year after baseline vs at baseline=2.30, 95 % CI: 1.28-4.15, p=0.005). Elevated baseline D-dimer levels emerged as a VTE-independent risk factor for mortality (HR=1.07, 95 % CI: 1.05-1.08, p< 0.001), and also predicted mortality risk in patients who developed VTE. A higher Khorana Score predicted both the risk for VTE and death, but did not predict mortality after cancer-associated VTE. In conclusion, multi-state modeling represents a very potent approach to time-to-VTE cohort data in the cancer population, and should be used for both observational and interventional studies on cancer-associated VTE.

Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS)

Data on the clinical course of lupus anticoagulant (LA)-positive individuals with or without thrombotic manifestations or pregnancy complications are limited. To investigate mortality rates and factors that might influence mortality, we conducted a prospective observational study of LA-positive individuals. In total, 151 patients (82% female) were followed for a median of 8.2 years; 30 of the patients (20%) developed 32 thromboembolic events (15 arterial and 17 venous events) and 20 patients (13%) died. In univariable analysis, new onset of thrombosis (hazard ratio [HR] = 8.76; 95% confidence interval [CI], 3.46-22.16) was associated with adverse survival. Thrombosis remained a strong adverse prognostic factor after multivariable adjustment for age and hypertension (HR = 5.95; 95% CI, 2.43-14.95). Concomitant autoimmune diseases, anticoagulant treatment at baseline, or positivity for anticardiolipin- or anti-β2-glycoprotein I antibodies were not associated with mortality. In a relative survival analysis, our cohort of LA positives showed a persistently worse survival in comparison with an age-, sex-, and study-inclusion-year-matched Austrian reference population. The cumulative relative survival was 95.0% (95% CI, 88.5-98.8) after 5 years and 87.7% (95% CI, 76.3-95.6) after 10 years. We conclude that occurrence of a thrombotic event is associated with higher mortality in patients with LA. Consequently, the prevention of thromboembolic events in LA positives might improve survival.

Single-stage revision for the infected total knee replacement: results from a single centre

Peri-prosthetic infection is amongst the most common causes of failure following total knee replacement (TKR). In the presence of established infection, thorough joint debridement and removal of all components is necessary following which new components may be implanted. This can be performed in one or two stages; two-stage revision with placement of an interim antibiotic-loaded spacer is regarded by many to be the standard procedure for eradication of peri-prosthetic joint infection. We present our experience of a consecutive series of 50 single-stage revision TKRs for established deep infection performed between 1979 and 2010. There were 33 women and 17 men with a mean age at revision of 66.8 years (42 to 84) and a mean follow-up of 10.5 years (2 to 24). The mean time between the primary TKR and the revision procedure was 2.05 years (1 to 8). Only one patient required a further revision for recurrent infection, representing a success rate of 98%. Nine patients required further revision for aseptic loosening, according to microbiological testing of biopsies taken at the subsequent surgery. Three other patients developed a further septic episode but none required another revision. These results suggest that a single-stage revision can produce comparable results to a two-stage revision. Single-stage revision offers a reduction in costs as well as less morbidity and inconvenience for patients.

Soluble Vascular Endothelial Growth Factor (sVEGF) and the Risk of Venous Thromboembolism in Patients with Cancer: Results from the Vienna Cancer and Thrombosis Study (CATS)

Purpose: Cancer patients are at an increased risk of venous thromboembolism (VTE). VEGF promotes the growth of highly thrombogenic tumor vessels. Here, we explored the utility of soluble plasma VEGF-A (sVEGF) as a biomarker for the prediction of VTE in patients with cancer. Experimental Design: Eight hundred four patients with newly diagnosed cancer or progression after remission were prospectively followed for 2 years until the occurrence of VTE or death [tumor sites: brain (n = 87), breast (n = 137), lung (n = 120), gastrointestinal (n = 143), pancreas (n = 53), prostate (n = 95), kidney (n = 22), myeloma and lymphoma (n = 99), and others (n = 48)]. Primary endpoint was symptomatic or fatal VTE. sVEGF was measured by immunoassay in baseline plasma. Results: Fifty-five patients developed VTE (6.8%) and 364 patients (45.3%) died. Five-hundred and forty-two (68.3%) participants had sVEGF levels above the detection limit of 0.5 pg/mL. The median sVEGF level (25th–75th percentile) was 8.1 pg/mL (0–17.7). The cumulative 2-year incidence of VTE was 10.2% [95% confidence interval (CI), 6.4–14.9] in patients with sVEGF greater than the 75th percentile of the sVEGF distribution (Q3, cutoff: 17.7 pg/mL), and 5.9% (95% CI, 4.2–7.9) in patients with lower levels (P = 0.03). The corresponding 2-year risk of death was 52.8% (95% CI, 46.0–60.0) and 43.9% (95% CI, 40.0–48.0), respectively (P = 0.02). In univariable time-to-VTE regression, elevated sVEGF was associated with VTE [subhazard ratio (SHR) per 10 pg/mL increase, 1.04; 95% CI,1.00–1.09; P = 0.04)]. The association between sVEGF and risk of VTE prevailed after multivariable adjustment for high-risk tumor sites, age, gender, factor VIII, thrombin generation potential, and soluble P-Selectin (adjusted SHR, 1.04; 95% CI, 1.00–1.09, P = 0.05). Conclusions: Elevated sVEGF is associated with an increased risk of VTE in patients with cancer. Clin Cancer Res; 22(1); 200–6. ©2015 AACR.

Hemoglobin, alkalic phosphatase, and C-reactive protein predict the outcome in patients with liposarcoma

Data on prognostic biomarkers in soft tissue sarcomas are scarce. The aim of the study was to define prognostic markers in patients with a liposarcoma, a subtype of sarcoma derived from adipose tissue. We restrospectively reviewed 85 patients with liposarcoma treated at our department from May 1994 to October 2011. Kaplan–Meier curves, uni‐, and multivariable Cox proportional hazard models and competing risk analysis were performed to evaluate the association between putative biomarkers with disease‐specific and overall survival. We observed a significant association between both alkalic phosphatase (ALP; subhazard ratio [SHR] per 1 unit increase: 1.35; 95%CI 1.10–1.65; p = 0.005) and C‐reactive protein (CRP; SHR per 1 mg/dl increase: 2,57; 95%CI 1.36–4,86; p = 0.004) with disease‐specific survival. Hemoglobin (Hb) (HR per 1 g/dl increase: 065; 95%CI 0.48–0.87; p = 0.003) was associated with overall survival. These associations prevailed after multivariable adjustment for AJCC tumor stage. This study identifies CRP and ALP as novel independent predictors of disease‐specific survival in patients with liposarcoma.

Statins are Associated with Low Risk of Venous Thromboembolism in Patients with Cancer: A Prospective and Observational Cohort Study

INTRODUCTION Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study. MATERIALS AND METHODS Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE. RESULTS Patients (n=1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n=96) and atorvastatin (n=48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p=0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Grays test: p=0.04). CONCLUSION This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials.