Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study.

BACKGROUND: Vitamin B(12) deficiency occurs frequently, especially among the elderly. However, screening for vitamin B(12) deficiency is hampered by poor sensitivity of the existing total vitamin B(12) assay. Methylmalonic acid (MMA) is considered as the most representative indicator of metabolic vitamin B(12) deficiency and is used as such in this study. The aim of this study was to validate the clinical usefulness of holotranscobalamin (holoTC) as an initial screening assay for metabolic vitamin B(12) deficiency in a mixed patient population. METHODS: Three hundred and sixty blood samples were collected by five Dutch hospitals. Vitamin B(12) and holoTC in serum were measured (AxSYM; Abbott). MMA in serum was measured by tandem mass spectrometry (LC-MS/MS). RESULTS: Receiver operating curve (ROC) analysis demonstrated a greater area under the curve (AUC) for holoTC than for vitamin B(12) in detecting vitamin B(12) deficiency characterized by three predefined cut-off levels of MMA. A cut-off value of 32 pmol/L of holoTC resulted in the highest sensitivity (83%) with acceptable specificity (60%) in detecting MMA concentrations above 0.45 µmol/L. The combination of vitamin B(12) and holoTC did not improve diagnostic accuracy at this cut-off level. CONCLUSIONS: HoloTC has a better diagnostic accuracy than vitamin B(12) and can replace the existing vitamin B(12) assay as a primary screening test in patients suspected of vitamin B(12) deficiency. Critical evaluation of cut-off values of holoTC indicated that a cut-off value of 32 pmol/L can be considered in screening for metabolic vitamin B(12) deficiency (defined by MMA > 0.45µmol/L) in a mixed patient population.

Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: the Rotterdam study.

BACKGROUND: In The Netherlands, costs of HMG-CoA reductase inhibitor (statin) use have recently increased sharply compared with costs of other drugs. However, several studies have established both undertreatment and non-guidelines-indicated treatment with statins, suggesting a suboptimal use of resources. OBJECTIVE: To estimate the drug costs associated with non-guidelines-indicated treatment and undertreatment with statins in an elderly population. PATIENTS AND SETTING: Data were obtained from the Rotterdam Study, a population-based prospective cohort study which began in 1990 with 7983 participants aged > or =55 years. Subjects with a history of cardiovascular disease (CVD) were excluded. Pharmacy records were used to assess patterns of medication use in daily medical practice. MAIN OUTCOME MEASURE: Non-guidelines-indicated treatment and undertreatment with statins were established in relation to Dutch cholesterol management guidelines for all participants. We calculated the costs of statin therapy associated with non-guidelines-indicated treatment, and the costs of statins if all those undertreated were to receive statins. The results were projected on to the Dutch population to determine the economic implications of non-adherence to cholesterol management guidelines in the elderly. RESULTS: Of the participants who started treatment with statins for the primary prevention of CVD during follow-up, 69% received non-guidelines-indicated treatment. More men (7.5%) were undertreated than women (1.6%) and more women (6.2%) received non-guidelines-indicated treatment than men (1.5%). Among the participants without CVD who were still alive at 1 January 2002, 14% were eligible for statin therapy but were untreated. After projection of the prevalence of non-guidelines-indicated treatment and undertreatment to the Dutch population, the absolute costs for non-guidelines-indicated treatment with statins in 2005 were estimated to be approximately 23 million euro(uncertainty limits [UL]: 19-28 million euro), while the cost to eliminate undertreatment was also 23 million euro (UL: 19-28 million euro). CONCLUSION: Reallocation of resources used for statin therapy from those receiving non-guidelines-indicated treatment to those being undertreated could lead to a more efficient use of resources.

Different accuracies of rapid enzyme-linked immunosorbent, turbidimetric, and agglutination D-dimer assays for thrombosis exclusion: impact on diagnostic work-ups of outpatients with suspected deep vein thrombosis and pulmonary embolism.

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1%, with a negative predictive value of more than 99 to 100% during 3-month follow-up. Compression ultrasonography (CUS) and spiral computed tomography (CT) currently are the methods of choice to confirm or rule out deep venous thrombosis (DVT) and pulmonary embolism (PE), respectively. CUS has a negative predictive value (NPV) of 97 to 98%, indicating the need to improve the diagnostic work-up of patients with suspected DVT by clinical score assessment and D-dimer testing. Spiral CT as a stand-alone method detects all clinically relevant PEs and a large number of alternative diagnoses. It rules out PE with a NPV of 98 to 99%. Spiral CT is expensive, emphasizing the need to improve the diagnostic work-up of patients with suspected PE by the use of clinical score assessment and D-dimer testing. Clinical score assessment for DVT and PE has not safely ruled out VTE in multicenter studies and in routine daily practices. Modification of the Wells clinical score assessment for DVT by elimination of the "minus 2 points" for alternative diagnosis will improve the reproducibility of the clinical score assessment. The combination of a first negative CUS and a negative SimpliRed or an enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer of < 1,000 ng/mL safely exclude DVT (NPV > 99%) irrespective of clinical score assessment and without the need to repeat CUS in approximately 60 to 70% of patients. The rapid quantitative and qualitative agglutination D-dimer assays for the exclusion of VTE are not sensitive enough as stand-alone tests and should be used in combination with clinical score assessment. A normal rapid ELISA VIDAS D-dimer test as a stand-alone test safely excludes DVT and PE, with a NPV of 99 to 100%, irrespective of clinical score, without the need of CUS or spiral CT. The combined strategy of a rapid ELISA VIDAS D-dimer followed by objective testing with CUS for DVT and by spiral CT for PE will reduce the need for noninvasive imaging techniques by 40 to 50%.

Prescribing behaviour according to Dutch and European guidelines on the management of hypercholesterolaemia (1992-1999).

BACKGROUND: The success of the full implementation of a new guideline may depend on the observed discrepancy between daily medical practice developed before the release of the guideline and new treatment recommendations issued by the guideline. AIM: To assess whether the initiation of statin treatment for primary prevention of cardiovascular disease in an elderly population was in agreement with guidelines. METHODS: Data were obtained from the Rotterdam Study, a prospective population-based cohort study consisting of 7983 subjects aged>or=55 years. In the period 1992-1999, all patients starting statins for primary prevention were selected. Treatment eligibility was established according to Dutch guidelines based on considerations of cost effectiveness (1998) and European guidelines based on clinical effectiveness (1998 and 2003). RESULTS: Only 5.7% [95% confidence interval (CI) 3.1, 8.3] of the 299 subjects starting statins for primary prevention met the eligibility criteria of the Dutch guidelines. Most patients (92.0%, 95% CI 88.9, 95.1) met the criteria of the 2003 European guidelines. Patients who did not meet any eligibility criteria were female and had one or less cardiovascular risk factor, except for two patients with total cholesterol levels<5 mmol l-1 prior to start of statin therapy. CONCLUSIONS: The use of statins was in agreement with the most recent European guidelines in over 90% of elderly patients who started statins for primary prevention, but in only 6% of these patients according to the Dutch guidelines. As long as existing guidelines are as discrepant as they are now, variation in agreement between physicians' prescribing and guideline recommendations is unavoidable.

Screening for deep vein thrombosis and pulmonary embolism in outpatients with suspected DVT or PE by the sequential use of clinical score: a sensitive quantitative D-dimer test and noninvasive diagnostic tools.

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1% during 3-month follow-up. The negative predictive value (NPV) during 3 months of follow-up is 98.1 to 99% after a normal venogram, 97 to 98% after a normal compression ultrasonography (CUS), and > 99% after serial CUS testing. Serial CUS testing is safe but 100 CUS must be repeated to find one or two CUS positive for deep vein thrombosis (DVT), which is not cost-effective and indicates the need to improve the diagnostic workup of DVT by the use of clinical score assessment and D-dimer testing. The NPV varies from 97.6 to 99.4% for low clinical score followed by a negative SimpiRED test, indicating the need for a first CUS. The NPV is 98.4 to 99.3% for a normal rapid enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer test result (< 500 ng/mL) irrespective of clinical score. The NPV is more than 99% for a negative CUS followed by either a negative SimpiRED test or an ELISA VIDAS test result of < 1000 ng/mL without the need to repeat a second CUS within 1 week. The sequential use of a sensitive, rapid ELISA D-dimer and clinical score assessment will safely reduce the need for CUS testing by 40 to 60%. Large prospective outcome studies demonstrate that with one negative examination with complete duplex color ultrasonography (CCUS) of the proximal and distal veins of the affected leg with suspected DVT, it is safe to withhold anticoagulant treatment, with a negative predictive value of 99.5%. This may indicates that CCUS is equal to serial CUS or the combined use of clinical score, D-dimer testing, and CUS. Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but not for subsegmental PE. A normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test safely excludes PE. Helical spiral computed tomography (CT) detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with suspected PE and can replace both the ventilation perfusion scan and pulmonary angiography to safely rule in PE and to rule out PE with an NPV of > 99%. The combination of clinical assessment, a rapid ELISA VIDAS D-dimer, followed by CUS will reduce the need for helical spiral CT by 40 to 50%.

Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants.

INTRODUCTION: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction. METHODS: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype. RESULTS: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele. CONCLUSIONS: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.

Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants.

OBJECTIVE: Vitamin K is an essential cofactor for the synthesis of several blood coagulation factors. It has been suggested that the apolipoprotein E (ApoE) genotype has profound effects on vitamin K status. Therefore, we investigated whether this common genetic polymorphism influenced dose requirements and effects of coumarin anticoagulants. METHODS: We did a cohort study in 1637 patients from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon. RESULTS: To attain the same level of anticoagulation, patients with genotype epsilon4/epsilon4 and genotype epsilon3/epsilon4 required respectively 3.4 mg (95%CI: -6.0 to -0.9) and 0.8 mg (95%CI: -1.6 to 0.1) acenocoumarol per week less than patients with genotype epsilon3/epsilon3. Patients homozygous for the epsilon2 allele required 3.5 mg (95%CI: 0.1 to 6.9) acenocoumarol per week more than patients with genotype epsilon3/epsilon3. The acenocoumarol maintenance dose showed a gene dose effect of the epsilon4 allele, but not of the epsilon2 allele. No significant dose difference was observed for phenprocoumon, possibly because of low numbers. CONCLUSION: The ApoE genotype affects the dose requirements of acenocoumarol.

The risk of overanticoagulation in patients with heart failure on coumarin anticoagulants.

Heart failure has been identified as a risk factor for increased coumarin anticoagulant responsiveness in several small-scale experiments. Epidemiological studies quantifying the risk of overanticoagulation by heart failure in a non-selected population on coumarins are scarce. Therefore, we investigated whether patients with heart failure have an increased risk of overanticoagulation and determined the effect of incidental heart failure on coumarin dose requirements. A cohort study of all patients was performed from an outpatient anticoagulation clinic treated with acenocoumarol or phenprocoumon between 1 January 1990 and 1 January 2000. All cohort members were followed until the first occurrence of an international normalized ratio (INR) > or = 6.0, the last INR assessment, death, loss to follow-up, or end of the study period. Of the 1077 patients in the cohort, 396 developed an INR > or = 6.0. The risk of overanticoagulation was 1.66 [95% confidence interval (CI): 1.33-2.07] for cases of prevalent heart failure and 1.91 (95%CI: 1.31-2.79) for incidental cases. The decrease in dose requirements in patients with incidental heart failure showed a significant trend from the fifth INR measurement preceding the date of incidental heart failure to the third measurement after this date. Heart failure is an independent risk factor for overanticoagulation. Therefore, patients with heart failure should be closely monitored to prevent potential bleeding complications.

The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.