We aimed to determine whether (1) patients with obstructive pulmonary disease (OPD) have an increased risk of sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF), and (2) the SCA risk is mediated by cardiovascular risk-profile and/or respiratory drug use.A community-based case-control study was performed, with 1310 cases of SCA of the ARREST study and 5793 age, sex and SCA-date matched non-SCA controls from the PHARMO database. Only incident SCA cases, age older than 40 years, that resulted from unequivocal cardiac causes with electrocardiographic documentation of VT/VF were included. Conditional logistic regression analysis was used to assess the association between SCA and OPD. Pre-specified subgroup analyses were performed regarding age, sex, cardiovascular risk-profile, disease severity, and current use of respiratory drugs.A higher risk of SCA was observed in patients with OPD (n = 190 cases [15%], 622 controls [11%]) than in those without OPD (OR adjusted for cardiovascular risk-profile 1.4 [1.2-1.6]). In OPD patients with a high cardiovascular risk-profile (OR 3.5 [2.7-4.4]) a higher risk of SCA was observed than in those with a low cardiovascular risk-profile (OR 1.3 [0.9-1.9]) The observed SCA risk was highest among OPD patients who received short-acting β2-adrenoreceptor agonists (SABA) or anticholinergics (AC) at the time of SCA (SABA OR: 3.9 [1.7-8.8], AC OR: 2.7 [1.5-4.8] compared to those without OPD).OPD is associated with an increased observed risk of SCA. The most increased risk was observed in patients with a high cardiovascular risk-profile, and in those who received SABA and, possibly, those who received AC at the time of SCA.

Background:

Lipid-lowering treatment with statins has proven to be effective in reducing cardiovascular events and mortality. In daily practice, however, adherence to medication is often low and this compromises the therapeutic effect. The aim of this study was to assess the effectiveness of an electronic reminder device (ERD) with or without counseling to improve refill adherence and persistence for statin treatment in non-adherent patients.

Methods:

A multicenter, community pharmacy-based, randomized controlled trial was conducted in 24 pharmacies in the Netherlands among patients with pre-baseline refill adherence rates between 50 and 80%. Eligible patients aged 65 years or older were randomly assigned to 1 of 3 groups: (1) counseling with an ERD (n = 134), (2) ERD with a written instruction (n = 131), and a (3) control group that received the usual treatment (n = 134). Main outcome measure: refill adherence to statin treatment for a 360-day period after inclusion (PDC360). Patients with a refill rate ≥80% were considered adherent. The effect among subgroups was also assessed.

Results:

There were no relevant differences at baseline. In the counseling with ERD group 54 of 130 eligible patients received the counseling with ERD. In the ERD group, 117 of 123 eligible patients received the ERD. The proportions of adherent patients in the counseling with ERD-group (69.2%) and in the ERD group (72.4%) were not higher than in the control group (64.8%). Among women using statins for secondary prevention, more patients were adherent in the ERD group (86.1%) than in the control group (52.6%) (p < 0.005). In men using statins for secondary prevention the ERD was found to have no effect.

Conclusion:

In this randomized controlled trial, no statistically significant improvement of refill adherence was found if an ERD was used with or without counseling. However, in a subgroup of women using statins for secondary prevention the ERD did improve adherence significantly.

BACKGROUND::

A distributed research network (DRN) of electronic health care databases, in which data reside behind the firewall of each data partner, can support a wide range of comparative effectiveness research (CER) activities. An essential component of a fully functional DRN is the capability to perform robust statistical analyses to produce valid, actionable evidence without compromising patient privacy, data security, or proprietary interests.

OBJECTIVES

AND

METHODS::

We describe the strengths and limitations of different confounding adjustment approaches that can be considered in observational CER studies conducted within DRNs, and the theoretical and practical issues to consider when selecting among them in various study settings.

RESULTS::

Several methods can be used to adjust for multiple confounders simultaneously, either as individual covariates or as confounder summary scores (eg, propensity scores and disease risk scores), including: (1) centralized analysis of patient-level data, (2) case-centered logistic regression of risk set data, (3) stratified or matched analysis of aggregated data, (4) distributed regression analysis, and (5) meta-analysis of site-specific effect estimates. These methods require different granularities of information be shared across sites and afford investigators different levels of analytic flexibility.

CONCLUSIONS::

DRNs are growing in use and sharing of highly detailed patient-level information is not always feasible in DRNs. Methods that incorporate confounder summary scores allow investigators to adjust for a large number of confounding factors without the need to transfer potentially identifiable information in DRNs. They have the potential to let investigators perform many analyses traditionally conducted through a centralized dataset with detailed patient-level information.

PURPOSE:

To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity.

METHODS:

An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance.

RESULTS:

Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed.

CONCLUSIONS:

Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.

PURPOSE:

We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1*15 haplotype in healthy volunteers.

METHODS:

In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19*1/*1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1*15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).

RESULTS:

Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.

CONCLUSIONS:

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.

Aim:

To investigate the cost-effectiveness of pharmacogenetic-guided phenprocoumon dosing versus standard anticoagulation care in Dutch patients with atrial fibrillation. Materials & methods: Using a decision-analytic Markov model, cost-effectiveness of pharmacogenetic-guided therapy versus standard care was estimated.

Results:

Compared with standard care, the pharmacogenetic-guided dosing strategy increased quality-adjusted life-years (QALYs) only very slightly and increased costs by €15. The incremental cost-effectiveness ratio was €2658 per QALY gained. In sensitivity analyses, the cost of genotyping had the largest influence on the cost-effectiveness ratio. In a probabilistic sensitivity analysis, the incremental costs of genotype-guided dosing were less than €20,000 per QALY gained in 75.6% of the simulations.

Conclusion:

Pharmacogenetic-guided dosing of phenprocoumon has the potential to increase health slightly and may be able to achieve this in a cost-effective way. Owing to the many uncertainties it is too early to conclude whether or not patients starting phenprocoumon should be genotyped. Original submitted 20 December 2012; Revision submitted 8 April 2013.

For the pending National Claims Database in Japan, researchers will not have access to death information in the enrollment files. We developed and evaluated a claims-based definition of death. METHODOLOGYPRINCIPAL FINDINGS: We used healthcare claims and enrollment data between January 2005 and August 2009 for 195,193 beneficiaries aged 20 to 74 in 3 private health insurance unions. We developed claims-based definitions of death using discharge or disease status and Charlson comorbidity index (CCI). We calculated sensitivity, specificity and positive predictive values (PPVs) using the enrollment data as a gold standard in the overall population and subgroups divided by demographic and other factors. We also assessed bias and precision in two example studies where an outcome was death. The definition based on the combination of discharge/disease status and CCI provided moderate sensitivity (around 60%) and high specificity (99.99%) and high PPVs (94.8%). In most subgroups, sensitivity of the preferred definition was also around 60% but varied from 28 to 91%. In an example study comparing death rates between two anticancer drug classes, the claims-based definition provided valid and precise hazard ratios (HRs). In another example study comparing two classes of anti-depressants, the HR with the claims-based definition was biased and had lower precision than that with the gold standard definition. CONCLUSIONSSIGNIFICANCE: The claims-based definitions of death developed in this study had high specificity and PPVs while sensitivity was around 60%. The definitions will be useful in future studies when used with attention to the possible fluctuation of sensitivity in some subpopulations.

In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was introduced in the Netherlands for all children aged 14 months. Despite its success, herd immunity may wane over time. Recently, a serogroup A,C,W135,Y meningococcal conjugate vaccine (MenACWY) was licensed for use in subjects of 12 months of age and above.To evaluate the cost-effectiveness of meningococcal vaccination at 14 months and an additional vaccination at the age of 12 years, both with the MenACWY vaccine.A decision analysis cohort model, with 185,000 Dutch newborns, was used to evaluate the cost-effectiveness of different immunization strategies. For strategies including a vaccination at 12 years of age, an additional cohort with adolescents aged 12 years was followed. The incremental cost-effectiveness ratio (ICER) was estimated for the current disease incidence and for a scenario when herd immunity is lost.Vaccination with MenACWY at 14 months is cost-saving. Vaccinating with MenACWY at 14 months and at 12 years would prevent 7 additional cases of meningococcal serogroup A,C,W135,Y disease in the birth cohort and adolescent cohort followed for 99 years compared to the current vaccine schedule of a single vaccination with MenC at 14 months. With the current incidence, this strategy resulted in an ICER of €635,334 per quality adjusted life year. When serogroup C disease incidence returns to pre-vaccination levels due to a loss of vaccine-induced herd-immunity, vaccination with MenACWY at 14 months and at 12 years would be cost-saving.Routine vaccination with MenACWY is cost-saving. With the current epidemiology, a booster-dose with MenACWY is not likely cost-effective. When herd immunity is lost, a booster-dose has the potential of being cost-effective. A dynamic model should be developed for more precise estimation of the cost-effectiveness of the prevention of disappearance of herd immunity.

AIM:

The aim of this study was to assess the effect of the CYP3A4 and OAT1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.

METHODS:

We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady-state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Therefore 16 healthy volunteers received therapeutic doses of bosentan (125 mg bid) for 14 days and clarithromycin (500 mg bid) concomitantly for the last 4 days and bosentan pharmacokinetics was assessed on days 1, 10, and 14.

RESULTS:

Clarithromycin significantly increased bosentan AUC0-τ 3.7-fold and Cmax 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.

CONCLUSION:

Clarithromycin substantially increases the exposure with bosentan suggesting that dose reductions may be necessary.