The prognostic value of the D-dimer test in cancer patients treated with and without low-molecular-weight heparin.
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Anticoagulants↗
Biomedical subjects
H R Büller
Publications and source records attributed to H R Büller.
Decision analysis for cancer screening in idiopathic venous thromboembolism.
BACKGROUND: The SOMIT trial randomized patients with idiopathic venous thromboembolism (IVTE) and without signs of cancer at routine medical examination, to extensive screening for cancer plus 2 years of follow-up or to just 2-year follow-up. METHODS: The data of the SOMIT-trial were used to perform a decision analysis. The screening tests were divided in several possible strategies. The number of detected cancer patients and the number of patients investigated further for an eventually benign condition were calculated for each strategy. The total costs for the screening strategy and for each detected cancer patient were determined. Based on the tumor type, stage, age and gender of the individual cancer patient, the difference in live years gained (LYG) was calculated between the two study groups. RESULTS: Computed tomography (CT) of the abdomen combined with sputum cytology and mammography detected 12 of the 14 patients with cancer and had one false-positive result. In general, screening strategies including abdominal/pelvic ultrasonography (US) or tumor markers yielded a higher number of patients needed to screen in comparison with those using abdominal/pelvic CT. Furthermore, the strategies which included colonoscopy, tumor markers, and abdominal/pelvic US were significantly more costly, had inferior LYG and higher costs per LYG, when compared with strategies using abdominal/pelvic CT. CONCLUSIONS: Despite the limitations of this analysis, the screening for cancer with a strategy including abdominal/pelvic CT with or without mammography and/or sputum cytology appears potentially useful for cancer screening in patients with IVTE. The cost-effectiveness analysis of this strategy needs confirmation in a large trial.
Cost-Benefit Analysis↗
Peripheral arterial disease: public and patient awareness in The Netherlands.
OBJECTIVE: To determine critical issues for future awareness programmes on peripheral arterial disease (PAD). DESIGN: National Dutch survey. MATERIALS AND METHODS: A representative sample of 1294 members of the general population, and 281 patients with PAD from the Capi@home database were administered a questionnaire concerning awareness of PAD. RESULTS: The response rate was 81% for the general population and 78% for patients with PAD. The familiarity with PAD terminology and symptoms amongst the general population was low. Few patients (20%) were aware that PAD was a disease of arteries. Amongst both the general population and the patient populations, PAD risk factors identification was low: hypertension (4% versus 0%); hypercholesterolaemia (9% versus 12%), diabetes (2% versus 8%), and smoking (27% versus 52%). Knowledge was moderate in both populations about treatment with exercise, but low for smoking cessation. The general population was unaware of the central role of general practitioners in the treatment of PAD. CONCLUSIONS: The awareness of symptoms, risk factors, and treatment options for PAD is low. Both population and patients needed only minimal information to relate PAD to other atherosclerotic diseases. Based on the results of this survey the Dutch Platform of Peripheral Arterial Disease together with the Dutch Heart Foundation are initiating the first awareness campaign on atherosclerosis.
Adult↗
Recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor/factor VIIa, attenuates coagulation and the interleukin-10 response in human endotoxemia.
The tissue factor-factor (F)VIIa complex (TF/FVIIa) is responsible for the initiation of blood coagulation under both physiological and pathological conditions. Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of TF/FVIIa, mechanistically distinct from tissue factor pathway inhibitor. The first aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of a single intravenous (i.v.) dose of rNAPc2. The second aim was to study its effect on endotoxin-induced coagulation and inflammation. Initially, rNAPc2 was administered to healthy volunteers in three different doses. There were no safety concerns and the pharmacokinetics were consistent with previous studies, in which rNAPc2 was administered subcutaneously. rNAPc2 elicited a dose-dependent reduction of the endogenous thrombin potential and a selective prolongation of prothrombin time. Subsequently, the effect on endotoxin-induced coagulation and inflammation was studied. The administration of rNAPc2 completely blocked the endotoxin-induced thrombin generation, as measured by plasma prothrombin fragment F1+2. The endotoxin-induced effect on fibrinolytic parameters such as plasmin-antiplasmin complexes and plasminogen activator inhibitor type 1 was not affected by rNAPc2. The administration of rNAPc2 attenuated the endotoxin-induced rise in interleukin (IL)-10, without affecting the rise in other cytokines. In conclusion, rNAPc2 is a potent inhibitor of TF/FVIIa, which was well tolerated and could safely be used intravenously in this Phase I study in healthy male volunteers. A single i.v. dose rNAPc2 completely blocked endotoxin-induced thrombin generation without affecting the fibrinolytic response. In addition, rNAPc2 attenuated the endotoxin-induced rise in IL-10, without affecting the rises in other cytokines.
Adolescent↗
Homocysteine and markers of coagulation and endothelial cell activation.
OBJECTIVES: In vitro studies suggest an influence of hyperhomocysteinemia on the coagulation system, but the influence of mild hyperhomocysteinemia in vivo is unclear. METHODS AND RESULTS: We studied the relation between homocysteine and markers of coagulation activation and endothelial cell activation in 279 patients with established atherosclerotic disease. In addition, we performed an investigator-blinded placebo-controlled cross-over study to investigate the influence of acute hyperhomocysteinemia by oral methionine load on these markers in 20 healthy volunteers. In the atherosclerotic patients prothrombin fragment F1+2 and soluble thrombomodulin (sTM) were associated with homocysteine in univariate analyses (P = 0.003 and P = 0.001, respectively), but not in multivariate analyses. Age, creatinine and MTHFR C677T polymorphism were major determinants of homocysteine concentration. MTHFR C677T polymorphism status was not associated with F1+2 and sTM. Median homocysteine concentrations increased in the healthy volunteers after methione load. However, after methionine load or after placebo, we did not observe different plasma concentrations of F1+2 (0.9 nmol L-1 vs. 0.9 nmol L-1, P = 0.39), d-dimer (153 micro g L-1 vs. 151 micro g L-1, P = 0.63) and von Willebrand factor (103% vs. 107%, P = 1.00). CONCLUSIONS: These results provide evidence against a major effect of mild hyperhomocysteinemia on activation of the coagulation system and endothelial cell activation in vivo.
Arteriosclerosis↗
Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.
BACKGROUND AND OBJECTIVES: The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect. PATIENTS AND METHODS: A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls. RESULTS AND CONCLUSIONS: In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.
Acenocoumarol↗
Non-invasive diagnostic work-up of patients with clinically suspected pulmonary embolism; results of a management study.
BACKGROUND: Clinicians often deviate from the recommended algorithm for the diagnosis of pulmonary embolism consisting of ventilation-perfusion scintigraphy and pulmonary angiography. OBJECTIVES: To assess the safety and feasibility of a diagnostic algorithm which reduces the need for lung scintigraphy and avoids the use of angiography. PATIENTS AND METHODS: Consecutive patients with a clinical suspicion of pulmonary embolism were prospectively investigated according to an algorithm in which the diagnosis of pulmonary embolism was excluded after a low clinical probability estimate and a normal d-dimer test result, a normal perfusion scintigraphy result, or a non-high probability scintigraphy result in combination with normal serial ultrasonography of the legs. In these patients anticoagulant treatment was withheld and they were followed up for 3 months to record possible thromboembolic events. During the study period, 923 consecutive patients were seen, of whom 292 were excluded because of predefined criteria. RESULTS: Of the 631 included patients, the diagnosis was refuted on the basis of a low clinical probability estimate and a normal d-dimer test result (95 patients), normal perfusion scintigraphy (161 patients) and non-high probability lung scintigraphy followed by normal serial ultrasonography (210 patients). Of these 466 patients, venous thromboembolic complications during follow-up occurred in six (complication rate 1.3%, 95% confidence interval 0.5, 2.8). The diagnostic protocol was completed in 92% of all included patients. CONCLUSION: The diagnosis of pulmonary embolism can be safely ruled out by a non-invasive algorithm consisting of d-dimer testing combined with a clinical probability estimate, lung scintigraphy, or serial ultrasonography of the legs (in case of non-diagnostic lung scintigraphy).
Algorithms↗
Has time come for screening for occult cancer in patients with venous thromboembolism?
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Humans↗
Observer variability in the assessment of clinical probability in patients with suspected pulmonary embolism.
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Humans↗
Beta-receptor blockade decreases elevated plasma levels of factor VIII:C in patients with deep vein thrombosis.
BACKGROUND: An elevated plasma level of factor VIII:C (FVIII:C) is a strong and dose-dependent risk factor for venous thromboembolism (VTE). The cause of elevated FVIII:C in patients with thrombophilia is as yet unknown. FVIII:C increases significantly after infusion of epinephrine, vasopressin or physical exercise. The aim of the present study was to investigate whether beta-receptor blockade will lower sustained elevated FVIII:C in patients with VTE. METHODS AND RESULTS: Two cohorts of patients with documented deep vein thrombosis and an elevated FVIII:C (>175 IU dL(-1)) and healthy volunteers, were studied. One cohort was treated with the beta-receptor blocker, whereas the other cohort served as non-treatment controls. The patient treatment group and healthy volunteers were given 40 mg propranolol, thrice daily, for 14 days. The mean baseline level of FVIII:C was 220 IU dL(-1) and 102 IU dL(-1) in patients and healthy volunteers, respectively. After 2 weeks of propranolol a significant 23% reduction of FVIII:C (- 52 IU dL(-1); 95%CI:[-65; -39]) compared with no change over time in the patient no- treatment group (-1.8 IU dL(-1); 95%CI:[-34; 30]). After discontinuation of propranolol FVIII:C returned to its initial high level. In healthy volunteers propranolol had no effect on the plasma concentration of FVIII:C. CONCLUSION: This study demonstrates that in patients with VTE a sustained elevated FVIII:C concentration can be decreased with the use of propranolol. This observation may be of potential clinical relevance, since it has been shown that each increase of 10 IU dL(-1) in FVIII:C concentration enhanced the risk of a recurrent VTE by 24%.
Adult↗
Soluble thrombomodulin in patients with established atherosclerosis.
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Arteriosclerosis↗
Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.
BACKGROUND: The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. METHODS: We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. RESULTS: Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. CONCLUSIONS: Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.
Aged↗
[Thrombosis prophylaxis in orthopaedic surgery: considerations and uncertainties].
As it is not always possible to identify patients at extra risk of deep-venous thrombosis after major orthopaedic surgery, it is considered advisable to prescribe prophylactic treatment. Prophylaxis with a low dose of unfractionated heparin is more effective than no prophylaxis at all but less effective than low molecular-weight heparin or cumarine derivatives. Acetylsalicylic acid does not appear to have a place in the prevention of venous thromboemboli in elective total-hip and total-knee surgery. Its usefulness in the operative treatment of hip fractures has not been established. Starting prophylaxis postoperatively has not been shown to be less safe or effective than starting it preoperatively. The incidence of thrombosis is lower if the course of prophylactic treatment is lengthened to 4-6 weeks following arthroplasty of the hip or knee. The optimal period of medicinal prophylaxis has yet to be ascertained. Intermittent pneumatic compression appears to be effective after total-knee arthroplasty but in practice is difficult to deliver. Support stockings, a foot pump and rapid mobilization have little effect on the incidence of proximal deep-venous thrombosis. There are insufficient data regarding the use of thrombosis prophylaxis in day surgery.
Anticoagulants↗
[New anticoagulants].
A large number of newly developed platelet aggregation inhibitors and anticoagulants are currently being investigated in clinical studies. Most of these new agents are targeted to haemostatic pathways that have recently been shown to be of importance in vivo and usually have a higher efficacy than the currently available anticoagulants. The new platelet aggregation inhibitors can be divided into thienopyridine derivatives (ticlopidine, clopidogrel) and glycoprotein IIb/IIIa receptor antagonists (abciximab, eptifibatide, tirofiban). The new inhibitors of fibrin synthesis can be divided into direct thrombin inhibitors (hirudine, melagatran, ximelagatran), specific factor Xa inhibitors (pentasaccharides: fondaparinux, idraparinux) and inhibitors of the tissue thromboplastin factor VIIa complex (recombinant nematode anticoagulant protein c2, inactivated factor VIIa, recombinant tissue factor pathway inhibitor). In some cases this also results in a (relatively modest) increase in the risk of bleeding. The clinical use of the new compounds is often much more convenient than that of the presently available anticoagulants.
Anticoagulants↗
Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism.
BACKGROUND: Despite effective treatment with anticoagulants, 2% to 7% of patients with pulmonary embolism will die as a result of their disease. METHODS AND RESULTS: We examined in 110 consecutive patients with pulmonary embolism whether plasma brain natriuretic peptide (BNP), a novel marker of (right) ventricular dysfunction, is a predictor of fatal pulmonary embolism. The relationship between BNP concentration measured at presentation and clinical outcome was assessed by comparing the proportion of outcome events among tertiles. Positive and negative predictive values of BNP levels in the highest and lowest tertiles were calculated. The risk of death related to pulmonary embolism if the BNP level is >21.7 pmol/L is 17% (95% CI, 6% to 33%). The negative predictive value for uneventful outcome of a BNP value <21.7 pmol/L is 99% (95% CI, 93% to 100%). CONCLUSIONS: This is the first study to show that plasma BNP levels seem to predict adverse outcome in patients with acute pulmonary embolism.
Humans↗
Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.
BACKGROUND: Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of the lower limbs. It is frequently treated by implantation of either an infrainguinal autologous (using the patient's own tissue) venous or artificial graft. A number of factors influence occlusion rates, including the material used. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. OBJECTIVES: To evaluate whether antiplatelet treatment in patients with symptomatic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival. SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group Specialised Register, (last searched April 2003), and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 1, 2003). Additional trials were sought through reference lists of papers and by reviewing proceedings from the vascular surgical society meetings. SELECTION CRITERIA: The methodological quality of each trial was assessed independently by two reviewers (JD, MMK), with emphasis on concealment of randomisation. DATA COLLECTION AND ANALYSIS: Details of the studies selected were extracted independently by two reviewers (JD, MMK), and an 'intention-to-treat' analysis performed. The treatment and control groups were compared for important prognostic factors and differences described. If any data were not available, further information was sought from the author. Data were synthesized by comparing group results. MAIN RESULTS: The administration of a variety of platelet-inhibitors resulted in improved venous and artificial graft patency compared to no treatment. However, analysing patients for graft-type indicated that patients receiving a prosthetic graft were more likely to profit from administration of platelet-inhibitors than those treated with a venous graft. REVIEWER'S CONCLUSIONS: Antiplatelet therapy with aspirin had a slight beneficial effect on the patency of peripheral bypasses, but seemed to have an inferior effect on venous graft patency compared with artificial grafts. The effect of aspirin on cardiovascular outcomes and survival was mild and not statistically significant; this might be due to the fact that the majority of patients receiving a peripheral graft have an advanced stage of PAD with critical ischemia. These patients are usually seriously ill with respect to cardiovascular diseases with high mortality rates of 20% per year. Additionally, the number of patients included in this analysis might still be too small to reach a statistically significant effect for mortality and cardiovascular morbidity.
Arteriosclerosis↗
Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery.
BACKGROUND: Chronic peripheral arterial disease (PAD) is frequently treated by implantation of either an infrainguinal autologous venous or artificial graft. One-year occlusion rates for infrainguinal bypasses vary between 15 and 75%, depending on the site of distal anastomosis, length, quality, and material of the graft, but also on other factors such as proximal inflow and distal outflow conditions. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. OBJECTIVES: To evaluate whether antithrombotic treatment in patients with chronic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival by performing a meta-analysis of performed RCTs. SEARCH STRATEGY: The search strategy was that adopted by the Cochrane Review Group on Peripheral Vascular Diseases. Additional data bases were reviewed (Reference lists of papers resulting from this search, MEDLINE from 1966-onwards and EMBASE from 1980-onwards using the terms 'anticoagulant' and 'arterial surgery'. SELECTION CRITERIA: The methodological quality of each trial was assessed independently by at least two reviewers using the checklist provided by the Peripheral Vascular Diseases Collaborative Review Group, with emphasis on concealment of randomisation. Each trial was given an allocation score of A (clearly concealed), B (unclear if concealed), or C (clearly not concealed) and a summary score of A (low risk of bias), B (moderate risk), or C (high risk). Trials scoring A were included and those scoring C were excluded. For a trial scoring B, an attempt was made to obtain more information by contacting the author. DATA COLLECTION AND ANALYSIS: For each trial, the number of patients originally allocated to each treatment group was extracted from the data and an 'intention to treat' analysis performed. Data collection on each trial included inclusion and exclusion criteria, patient details, type of graft, type and dose of antithrombotic therapy used, outcome, and side effects. The treatment and control groups were compared for important prognostic factors and differences described. If any of the above data was not available, further information was sought from the author. However, the heterogeneity between trials could not be tested due to inaccessible data. Data were synthesized by comparing group results. MAIN RESULTS: The analysis including four trials which evaluated vitamin K antagonists (VKA) versus no VKA indicate, that oral anticoagulation tendentially favours venous but not artificial graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin or aspirin/dipyridamole supported evidence for a positive effect of VKA on the patency of venous but not artificial grafts. Subgroup analysis for artificial grafts as performed in one trial showed a favourable effect of antiplatelet agents on synthetic bypasses. In two trials with a relatively small number of patients low molecular weight heparin treatment was associated with a lower incidence of early postoperative graft thrombosis compared to treatment with unfractionated heparin. In one trial infusion of antithrombin concentrate was reported to have a negative effect on intraoperative graft thrombosis necessitating the study to be stopped before termination. Perioperative administration of ancrod was compared to unfractionated heparin showing no benefit of one drug compared to the other. REVIEWER'S CONCLUSIONS: Patients operated for an infrainguinal venous graft might benefit from treatment with VKA, whereas patients receiving an artificial graft might profit more from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers comparing antithrombotic therapies with either placebo or antiplatelet therapies are called for in the future.
Arteriosclerosis↗
Can causes of false-normal D-dimer test [SimpliRED] results be identified?
BACKGROUND: To simplify the diagnostic strategy of patients suspected for venous thromboembolism, the use of D-dimer tests has been advocated. Very important for the safety of such diagnostic strategies would be the capacity to recognise false-normal D-dimer results, in order to prevent inadequately withholding anticoagulant treatment in patients who actually have the disease. Insight in the causes of false-normal D-dimer results would therefore be necessary. We hypothesised that certain patient characteristics are associated with relatively low plasma D-dimer levels and, therefore, could increase the risk of false-normal results. METHODS: Consecutive patients with an objectively confirmed venous thromboembolic event and an independently obtained false-normal SimpliRED D-dimer test result were included in the study. For each patient, two controls with objectively confirmed venous thromboembolism and an adequate abnormal D-dimer result were selected. Baseline patient characteristics, obtained by standardised questionnaires, were compared between the two groups of patients. RESULTS: In total, 686 patients had a venous thromboembolic event and 47 of these patients had a false-normal SimpliRED result. Therefore, the overall sensitivity of the SimpliRED test for venous thromboembolism was 94% (95% CI: 92-95%). Although the prevalence of certain clinical characteristics was significantly higher in patients with a false-normal D-dimer result than in the controls [odds ratios for (LMW)heparin treatment and symptoms lasting more than 10 days: 5.1 (95% CI: 1.5-18.7) and 3.2 (95% CI:1.4-7.4), respectively], the prevalence of these characteristics was also high in the control group with an adequate abnormal D-dimer. Combining two or more of these characteristics had a low prevalence and did not further improve the ability to identify those patients with a false-normal D-dimer test at presentation. CONCLUSIONS: Although these findings clearly indicate an association between certain baseline clinical characteristics and the occurrence of a false-normal SimpliRED test, the clinical utility for these characteristics is limited.
Adult↗