Felix J. M. van der Meer

Infectious Complications of Central Venous Catheters Increase the Risk of Catheter-Related Thrombosis in Hematology Patients: A Prospective Study

PURPOSE We studied whether the risk of central venous catheter (CVC) -related thrombosis increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Secondly, we determined whether thrombosis can be predicted or excluded by CVC lock fluid surveillance cultures. PATIENTS AND METHODS In a prospective setting, 105 consecutive patients were carefully examined for CVC-related infection and thrombosis. In all patients, microbial surveillance cultures of CVC lock fluid were taken every other day. All patients with clinical suspicion of CVC-related thrombosis underwent Doppler ultrasound or additional venography. RESULTS The cumulative incidence of CVC-related infection was 24% (25 of 105 patients). Clinically manifest thrombosis occurred in 13 (12%) of 105 patients. In patients with CVC-related infection, the risk of thrombosis increased markedly in comparison to those without infection (relative risk, 17.6; 95% CI, 4.1 to 74.1). In patients having two or more positive subsequent CVC lock fluid cultures with identical micro-organisms, 71.4% developed thrombosis, as compared with 3.3% in patients with negative or a single positive culture. CONCLUSION The risk of clinically manifest thrombosis is increased after an episode of CVC-related infection in patients undergoing intensive chemotherapy. Surveillance culturing of CVC lock fluid may be clinically useful in estimating the risk for thrombosis and the instigation of focused early intervention.

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia

Objective—Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin. Methods and Results—Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year. Conclusions—Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.

Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon

Summary.  To investigate whether the different pharmacokinetics of acenocoumarol (t1/2 = 11 h) and phenprocoumon (t1/2 = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty‐eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient‐years. Quality of OAT calculated over the whole treatment period was higher with phenprocoumon as expressed by the number of INR checks in the therapeutic range (phenprocoumon: 42·7%, acenocoumarol: 36·5%, difference: 6·1%, CI95 of the difference: 3·0–9·3%) and by time in range (phenprocoumon: 46·6%, acenocoumarol: 41·6%, difference: 5·0%, CI95 of the difference: 1·3–8·6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6·1%, CI95: 1·8–10·4%). The incidence of severe bleeding complications was similar (phenprocoumon: 0·04/patient/year vs acenocoumarol: 0·03/patient/year) with a slight excess of minor bleeds with phenprocoumon (0·19/patient/year vs 0·06/patient/year). We conclude that phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, phenprocoumon is preferable to acenocoumarol for prolonged OAT.

Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon

Variability in the control of oral anticoagulant therapy has been associated with a heightened risk of complications. We compared control of anticoagulation between two commonly used coumarins, phenprocoumon and acenocoumarol, and among anticoagulation clinics. All qualifying patients were managed at six regional anticoagulation clinics in the Netherlands. This retrospective cohort study compiled data during a three-year period from a computerised dosing and management system. Anticoagulation control was expressed as the percent of time within the therapeutic range and stability expressed as the time-weighted variance in the international normalised ratio (INR). Data were available for 22,178 patients of whom 72% were treated with acenocoumarol. INRs of patients who received phenprocoumon were within the therapeutic range 50% of the time compared with 43% for acenocoumarol (OR 1.32, 95% CI 1.24-1.41). Moreover, patients on phenprocoumon required 15% fewer monitoring visits and had more stable INR values. These observations were consistent for all six clinics. There were also sizable differences between the clinics with respect to control and stability of anticoagulation that were stable from year-to-year and were unrelated to the drug used. With its longer half-life of three to five days, phenprocoumon produces more stable anticoagulation than acenocoumarol and should generally be the drug of choice when these are the available choices. The differences observed among clinics suggest that certain clinics employ policies and practices resulting in better control of anticoagulation.

Central venous catheter related thrombosis in haematology patients and prediction of risk by screening with Doppler-ultrasound.

Summary. Patients with a central venous catheter (CVC) who receive intensive chemotherapy or a stem cell transplantation for haematological disease are at risk for developing CVC‐related thrombosis. To study the incidence of thrombosis, 105 consecutive patients underwent serial Doppler‐ultrasound and we evaluated whether clinically manifest thrombosis could be predicted by screening with Doppler‐ultrasound. Patients with subclavian or jugular inserted CVCs were clinically assessed each day for signs and symptoms of thrombosis. Additional Doppler‐ultrasound screens were performed weekly by an independent physician in all patients until CVC removal. Doppler‐ultrasound recordings were assessed by two blinded observers. In cases of clinically suspected thrombosis, the attending physicians followed routine diagnostic and therapeutic procedures. The overall cumulative incidence of CVC‐related thrombosis was 28·6% (30 of 105 patients). Of the 30 patients with thrombosis, 26 had subclinical thrombosis by Doppler‐ultrasound, nine of whom developed clinically manifest thrombosis later. Four patients had clinically manifest thrombosis without prior abnormal Doppler‐ultrasound. In cases of subclinical thrombosis the risk of developing symptomatic disease increased sevenfold (34·6% vs. 5·1%). Doppler‐ultrasound screening may be useful to identify those patients that are at high and low risk for clinically manifest CVC‐related thrombosis.

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status

Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment.

Using the common-sense model to predict risk perception and disease-related worry in individuals at increased risk for venous thrombosis.

OBJECTIVE This study applied the Common-Sense Model (CSM) to predict risk perception and disease-related worry in 174 individuals with a genetic predisposition to venous thrombosis (thrombophilia). DESIGN Participants completed an adapted version of the Illness Perception Questionnaire-Revised (IPQ-R) and measures assessing risk perception and worry. RESULTS Regression analyses revealed that illness perceptions were predictors of risk perception and thrombosis worry. The hypothesis that illness perceptions mediate the relationship between a persons experience of venous thrombosis and perceived risk and thrombosis worry could not be confirmed. CONCLUSIONS Further research should refine the IPQ-R for populations at risk of a disease and examine the value of the CSM in explaining the relationship between risk perception, worry, and health behavior.

Prevention of Coagulase-Negative Staphylococcal Central Venous Catheter–Related Infection Using Urokinase Rinses: A Randomized Double-Blind Controlled Trial in Patients With Hematologic Malignancies

PURPOSE Fibrin deposition at the intraluminal surface of the indwelling part of the central venous catheter (CVC) surface increases the risk of CVC-related coagulase-negative staphylococci (CoNS) infection. Therefore, repetitive enzymatic dissolution of fibrin by urokinase might reduce the risk of CVC-related infection. We undertook this study to investigate whether three times weekly urokinase rinsing of CVC reduces the incidence or severity of CVC-related infections by CoNS in patients undergoing intensive cytotoxic treatment for hematologic malignancies. PATIENTS AND METHODS In a double-blind setting, all consecutive patients with a CVC were randomly allocated to receive either urokinase rinses (5 mL of 5,000 U/mL) or placebo (saline), both three times weekly. RESULTS The percentage of patients with at least one positive culture with CoNS was lower in patients receiving urokinase compared with patients receiving placebo (26% v 42%, respectively; relative risk [RR] = 0.61; 95% CI, 0.39 to 0.94). Major CVC-related CoNS infection occurred less frequently in patients receiving urokinase versus placebo (1.2% v 14.1%, respectively; RR = 0.09; 95% CI, 0.01 to 0.50). Secondary complications, including CVC-related thrombosis, were observed less frequently in the urokinase group compared with the placebo group (1.3% v 9.0%, respectively; RR = 0.14; 95% CI, 0.02 to 0.82). No severe bleeding complications attributable to urokinase were observed. CONCLUSION Three times weekly urokinase rinsing reduces the incidence of CVC-related CoNS infection in patients treated with intensive cytotoxic therapy for hematologic malignancies, with acceptable safety.

The role of compliance as a cause of instability in oral anticoagulant therapy.

To assess the role of non‐compliance as a cause of instability in patients on oral anticoagulant therapy, a follow‐up study of stably and instably anticoagulated patients and of patients beginning oral anticoagulant therapy was performed. Compliance was assessed by pill counting and with the use of pill bottles in the cap of which a microprocessor registered the exact date and time of opening of the bottle. (In)stability of oral anticoagulant therapy was expressed as the number of INRs and as the time spent within the target range and by squared sigma. Subsequently, as a pilot study, a randomized intervention study in instable, non‐compliant patients was performed in which these patients were or were not informed about the real nature of the cap of the pill bottle.