Anthonius de Boer

Instrumental Variables Application and Limitations

To correct for confounding, the method of instrumental variables (IV) has been proposed. Its use in medical literature is still rather limited because of unfamiliarity or inapplicability. By introducing the method in a nontechnical way, we show that IV in a linear model is quite easy to understand and easy to apply once an appropriate instrumental variable has been identified. We also point out some limitations of the IV estimator when the instrumental variable is only weakly correlated with the exposure. The IV estimator will be imprecise (large standard error), biased when sample size is small, and biased in large samples when one of the assumptions is only slightly violated. For these reasons, it is advised to use an IV that is strongly correlated with exposure. However, we further show that under the assumptions required for the validity of the method, this correlation between IV and exposure is limited. Its maximum is low when confounding is strong, such as in case of confounding by indication. Finally, we show that in a study in which strong confounding is to be expected and an IV has been used that is moderately or strongly related to exposure, it is likely that the assumptions of IV are violated, resulting in a biased effect estimate. We conclude that instrumental variables can be useful in case of moderate confounding but are less useful when strong confounding exists, because strong instruments cannot be found and assumptions will be easily violated.

Rate and determinants of 10-year persistence with antihypertensive drugs

Objective To assess the proportion of patients starting with antihypertensive drug treatment who continued treatment for at least 10 years. Design A retrospective cohort study. Setting The PHARMO record linkage system containing drug dispensing records from community pharmacies and linked hospital discharge records of approximately 950 000 subjects. Participants Patients who started using antihypertensive drugs (two or more prescriptions) in 1992 and did not receive a prescription for any antihypertensive drug in the 365 days preceding the first prescription. Main outcome measure Persistence with antihypertensive drugs until 10 years. Results Among a total of 2325 patients who started using antihypertensive drugs, 39% used continuously during the 10 years of follow-up. Approximately 22% temporarily discontinued and restarted treatment, whereas 39% of patients discontinued permanently. Older patients were more persistent than younger patients [20–39 years: odds ratio (OR) 2.08; 95% confidence interval (CI) 1.52–2.84; 40–59 years: (reference), ≥ 60 years: OR 0.69; 95% CI 0.54–0.89]. More patients who started with diuretics (reference) and beta blockers (OR 1.15; 95% CI 0.87–1.52) discontinued compared with those who started with dihydropyridine calcium antagonists (OR 0.54; 95% CI 0.34–0.84), and angiotensin-converting enzyme (ACE) inhibitors (OR 0.38; 95% CI 0.27–0.55). Patients who started with combination therapy (OR 0.29; 95% CI 0.14–0.54 compared with diuretics) or patients who were initially treated by a cardiologist (OR 0.82; 95% CI 0.61–0.97) or internist (OR 0.80; 95% CI 0.62–0.98 compared with general practitioners) also showed higher persistence. Conclusion Long-term persistence in daily practice is low compared with persistence observed in randomized clinical trials and should be considered in the choice of a first-line antihypertensive agent.

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.).

VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.

Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

Comparison of different pain scoring systems in critically ill patients in a general ICU.

BackgroundPain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU.MethodsWe performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients (n = 113).ResultsInter-rater reliability of the NRS and BPS proved to be adequate (kappa = 0.71 and 0.67, respectively). The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS ≥4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found (rs = 0.84, P < 0.001). In ventilated patients, a moderate positive correlation was found between the NRS and the BPS (rs = 0.55, P < 0.001). However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low (median 3.0, range 3.0 to 5.0).ConclusionThe different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (≥4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patients pain. In ventilated patients, the BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.

CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case–control study

AIMS despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. METHODS AND RESULTS the selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (OR(adj): 1.7, 95% CI: 1.0-2.6, P = 0.018 and OR(adj): 2.4, 95% CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (OR(adj): 2.5, 95% CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (OR(adj): 3.3, 95% CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. CONCLUSION carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI.

Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing.

Abstract Objective: To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people. Design: Randomised controlled trial with three arms (individual visits, group visits, and a control arm). Setting: Southwest Netherlands. Participants: 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a database covering all prescriptions to people covered by national health insurance in the area (about 240 000). Intervention: All general practitioners and pharmacists in both intervention arms were offered two educational visits. For physicians in groups randomised to the individual visit arm, 43 of 70 general practitioners participated; in the group visit intervention arm, five of seven groups (41 of 52 general practitioners) participated. Main outcome measures: Numbers of elderly people (60 years) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants. Results: An intention to treat analysis found a 26% reduction in the rate of starting highly anticholinergic antidepressants in elderly people (95% confidence interval —4% to 48%) in the individual intervention arm and 45% (8% to 67%) in the group intervention arm. The use of less anticholinergic antidepressants increased by 40% (6% to 83%) in the individual intervention arm and 29% (—7% to 79%) in the group intervention arm. Conclusions: Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people. These approaches are practical means to improve prescribing by continuing medical education.

Influence of question structure on the recall of self-reported drug use.

Epidemiological studies often rely on self-reported information as a source of drug exposure. Several studies have evaluated the accuracy of self-reported information on drug use. The influence of question structure on the accuracy of recall, however, has not been studied extensively in these studies. In this study we examined the recall accuracy of questionnaire information on drug use in a ongoing public health survey with special attention to the influence of question structure on sensitivity of recall. A sample of 372 hypertensive subjects for whom questionnaire information and pharmacy records were available was examined. Self-reported information on drug use was obtained through questions about medications used for a specific condition and one final open-ended question. This information was compared with the pharmacy medication history. About 71% of all drugs that were currently in use according to the pharmacy records were recalled through the self-administered questionnaire, and 94% of all drugs mentioned in the questionnaire could be traced in the pharmacy records. Recall sensitivity was higher for questions about medications used for a specific indication (88%) than for the open-ended question (41%). The type of drug that was used might have caused part of this difference in recall. We conclude that questionnaire structure might be of influence on the accuracy of recall of self-reported drug use, and more attention should be paid to the structure of questions on drug use.

Risk of Hip/Femur Fracture After Stroke: A Population-Based Case-Control Study

Background and Purpose— Stroke increases the risk of hip/femur fracture, as seen in several studies, although the time course of this increased risk remains unclear. Therefore, our purpose is to evaluate this risk and investigate the time course of any elevated risk. Methods— We conducted a case-control study using the Dutch PHARMO Record Linkage System database. Cases (n=6763) were patients with a first hip/femur fracture; controls were matched by age, sex, and region. Odds ratio (OR) for the risk of hip/femur fracture was derived using conditional logistic regression analysis, adjusted for disease and drug history. Results— An increased risk of hip/femur fracture was observed in patients who experienced a stroke at any time before the index date (adjusted OR, 1.96; 95% CI, 1.65–2.33). The fracture risk was highest among patients who sustained a stroke within 3 months before the index date (adjusted OR, 3.35; 95% CI, 1.87–5.97) and among female patients (adjusted OR, 2.12; 95% CI, 1.73–2.59). The risk further increased among patients younger than 71 years (adjusted OR, 5.12; 95% CI, 3.00–8.75). Patients who had experienced a hemorrhagic stroke tended to be at a higher hip/femur fracture risk compared with those who had experienced an ischemic stroke. Conclusions— Stroke is associated with a 2.0-fold increase in the risk of hip/femur fracture. The risk was highest among patients younger than 71 years, females, and those whose stroke was more recent. Fall prevention programs, bone mineral density measurements, and use of bisphosphonates may be necessary to reduce the occurrence of hip/femur fractures during and after stroke rehabilitation.