Stefan Vegter

Sodium Intake, ACE Inhibition, and Progression to ESRD

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (<100 mEq/g), medium (100 to <200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of >4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P<0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (>14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

Pharmacoeconomic evaluations of pharmacogenetic and genomic screening programmes : A systematic review on content and adherence to guidelines

The fields of pharmacogenetics and pharmacogenomics have become important practical tools to progress goals in medical and pharmaceutical research and development. As more screening tests are being developed, with some already used in clinical practice, consideration of cost-effectiveness implications is important. A systematic review was performed on the content of and adherence to pharmacoeconomic guidelines of recent pharmacoeconomic analyses performed in the field of pharmacogenetics and pharmacogenomics.Economic analyses of screening strategies for genetic variations, which were evidence-based and assumed to be associated with drug efficacy or safety, were included in the review. The 20 papers included cover a variety of healthcare issues, including screening tests on several cytochrome P450 (CYP) enzyme genes, thiopurine S-methyltransferase (TMPT) and angiotensin-converting enzyme (ACE) insertion deletion (ACE I/D) polymorphisms.Most economic analyses reported that genetic screening was cost effective and often even clearly dominated existing non-screening strategies. However, we found a lack of standardization regarding aspects such as the perspective of the analysis, factors included in the sensitivity analysis and the applied discount rates. In particular, an important limitation of several studies related to the failure to provide a sufficient evidence-based rationale for an association between genotype and phenotype.Future economic analyses should be conducted utilizing correct methods, with adherence to guidelines and including extensive sensitivity analyses. Most importantly, genetic screening strategies should be based on good evidence-based rationales. For these goals, we provide a list of recommendations for good pharmacoeconomic practice deemed useful in the fields of pharmacogenetics and pharmacogenomics, regardless of country and origin of the economic analysis.

Clinical and economic impact of non- adherence in COPD: A systematic review

BACKGROUND Medication for Chronic Obstructive Pulmonary Disease (COPD) has shown to substantially reduce symptoms and slow progression of disease. However, non-adherence to medication is common and associated with worsened clinical and economic outcomes. OBJECTIVE The objective of this study was to perform a systematic review of published literature to assess the impact of non-adherence to COPD medication on clinical and economic outcomes. METHODS A search in PubMed and Web of Science databases was conducted of original studies published from database inception to 2012. Studies must report on the association between adherence to COPD medication and outcomes, published in English in peer-reviewed journals and full texts needed to be available. RESULTS Twelve full articles were included in the review. Most studies were retrospective database studies. Seven studies reported on the association between adherence and clinical outcomes, two on mortality, three on costs, four on quality of life and one on work productivity. Results indicated a clear association between adherence and both clinical and economic outcomes. Evidence from studies revealed increased hospitalizations, mortality, quality of life and loss of productivity among non-adherent patients. CONCLUSION This review revealed a clear association between non-adherence to COPD medication and worsened clinical and economic outcomes making non-adherent patients a priority for cost-effective interventions.

Cost-effectiveness of varicella vaccination programs : an update of the literature

Varicella is one of the most common infectious diseases in childhood, caused by the varicella zoster virus. Although vaccines are available, there are only a few countries with an early-childhood vaccination program. Most countries mainly focus on vaccination of high-risk groups, such as susceptible healthcare workers. One of the main concerns with a routine early-childhood vaccination program is a potential (temporal) increase of the incidence of herpes zoster among elderly adults. In this review, we focus on the cost–effectiveness of varicella vaccination and on the methodology used in the health–economic studies. In particular, we focus on the perspective adopted, type of model used, the modeled effect on herpes zoster, the vaccine efficacy and price, and on the value of time lost by infection. The vast majority of studies show vaccination of high-risk groups – including susceptible adolescents – to be cost saving. Routine early-childhood vaccination programs are always cost saving if indirect costs of production losses are included, or cost effective, as long as the potential negative effects on zoster are not taken into account. We note that most studies included in the review used old vaccine prices and a single dose of the varicella vaccine, whereas multiple doses are now becoming the standard. Despite that, those aspects limit the timeliness of our review and we believe that the current work does provide useful insights in the cost–effectiveness of varicella vaccination.

A Network Meta-Analysis of the Relative Efficacy of Treatments for Actinic Keratosis of the Face or Scalp in Europe

Background Several treatments are available for actinic keratosis (AK) on the face and scalp. Most treatment modalities were compared to placebo and therefore little is known on their relative efficacy. Objectives To compare the different treatments for mild to moderate AK on the face and scalp available in clinical practice in Europe. Methods A network meta-analysis (NMA) was performed on the outcome “complete patient clearance”. Ten treatment modalities were included: two 5-aminolaevulinic acid photodynamic therapies (ALA-PDT), applied as gel (BF-200 ALA) or patch; methyl-aminolevulinate photodynamic therapy (MAL-PDT); three modalities with imiquimod (IMI), applied as a 4-week or 16-week course with 5% imiquimod, or a 2–3 week course with 3.75% imiquimod; cryotherapy; diclofenac 3% in 2.5% hyaluronic acid; 0.5% 5-fluorouracil (5-FU); and ingenol mebutate (IMB). The only data available for 5% 5-FU was from one small study and was determined to be too limited to be reliably included in the analysis. For BF-200 ALA and MAL-PDT, data from illumination with narrow-band lights were selected as these are typically used in clinical practice. The NMA was performed with a random-effects Bayesian model. Results 25 trials on 5,562 patients were included in the NMA. All active treatments were significantly better than placebo. BF-200 ALA showed the highest efficacy compared to placebo to achieve total patient clearance. BF-200 ALA had the highest probability to be the best treatment and the highest SUCRA score (64.8% and 92.1%), followed by IMI 5% 4 weeks (10.1% and 74.2%) and 5-FU 0.5% (7.2% and 66.8%). Conclusions This NMA showed that BF-200 ALA, using narrow-band lights, was the most efficacious treatment for mild to moderate AK on the face and scalp. This analysis is relevant for clinical decision making and health technology assessment, assisting the improved management of AK.

Misdiagnosis and mistreatment of a common side-effect - angiotensin-converting enzyme inhibitor-induced cough

AIMS Angiotensin-converting enzyme inhibitors (ACEi) are frequently prescribed for various cardiovascular and renal diseases. A common side-effect of these drugs is a persistent dry cough. Physicians who fail to recognize a dry cough to be ACEi-related may attempt to treat it with antitussive agents instead of recommended ACEi substitution. Prescription behaviour in the general population considering treatment of the side-effect with antitussive agents has not been studied before. METHODS Drug dispensing data between 2000 and 2007 were retrieved from the IADB.nl database. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEi initiation than the other way around. A logistic regression model was fitted to determine predictors. RESULTS We identified 27 446 incident users of ACEi therapy. One thousand and fifty-four patients were incident users of both ACEi and antitussives within a half-year time span. There was an excess of patients being prescribed antitussive agents after ACEi initiation (703 vs. 351), adjusted sequence ratio 2.2 [confidence interval (CI) 1.9, 2.4]. Female patients were more likely to be prescribed antitussive agents following ACEi therapy initiation, odds ratio 1.4 (CI 1.1, 1.9), age and co-medications were not significant predictors. CONCLUSIONS There was a significant and clinically relevant excess of patients receiving antitussives after ACEi initiation. The results suggest that cough as a side-effect of ACEi is not recognized as being ACEi-related or is symptomatically treated with antitussive agents instead of ACEi substitution. The estimated frequency of antitussive treatment of ACEi-induced dry cough is 15%.

Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature

Objective Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. Methods A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies’ overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. Results We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. Conclusions Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests’ efficacy remains of utmost importance.

COPD in the working age population: The economic impact on both patients and government

Abstract Objectives: To explore the full economic impact, on both patients and government, as a result of COPD in the working age population. Methods: The economic impact of COPD due to medical treatment, impaired productivity and early retirement was assessed in a cross sectional cost analysis of the Dutch COPD population aged 45–64 years. The costing year was 2009 and input parameters were derived from both national data sources and the international COPD uncovered survey. Results: While direct medical costs for COPD patients of working age were relatively low (€91 million), the amount of lost productivity (income) due to early retirement (€223 million) exceeded over two times their medical costs. In addition, costs for the government were considerable because of lost tax revenues (€77 million) and COPD related disability pensions paid (€180 million). Apart from lost productivity due to early retirement, costs due to impaired productivity for working COPD patients were €63 million. Conclusions: The costs of COPD for both patients of working age as for the government were considerable, making this population a priority for prevention and intervention programs of healthcare providers, employers and government.

Economic evaluations of pharmacogenetic and genomic screening programs: update of the literature†

Pharmacogenetics and pharmacogenomics show great potential for developing individual treatment modalities to achieve optimal therapy effectiveness. Economic analyses are performed to determine whether pharmacogenetic screening strategies provide good value for money. The current review provides an update of published economic studies. Economic analyses of pharmacogenetic screening programs published between 2000 and July 2010 were included in the review. Information was extracted on research area, genetic information, type of economic analysis, key aspects of adherence to economic guidelines, costs and commercial availability of genetic tests, and the role of the funding party. A total of 42 economic studies on pharmacogenetic screening strategies were included. Over time, more cost‐utility analyses were performed, longer time windows were employed, and more extensive sensitivity analyses were conducted. Considerable differences in costs of screening tests for the same polymorphism were found, which often, but not always, had a large influence on the costs of screening strategies. Most studies were conducted from an academic or hospital perspective without direct links to pharmaceutical or diagnostic manufacturers. The quality of economic analyses of pharmacogenetic screening programs has improved over time. However, input variables are not always clearly described. In particular, substantial variation exists in the reported costs of the pharmacogenetic tests. Often these test costs are considered a major cost driver and could therefore be of particular importance for the interpretation of cost‐effectiveness results. Furthermore, the economic studies seem to be conducted to increase awareness of possibilities and perspectives of genetic testing rather than to influence policy decisions on reimbursement. Drug Dev Res 71: 492–501, 2010.  © 2010 Wiley‐Liss, Inc.

Proactive Pharmaceutical Care Interventions Improve Patients’ Adherence to Lipid-Lowering Medication

Bachground: Lipid-lowering drugs are effective preventive medication for patients at risk of cardiovascular complications. However, medication adherence is suboptimal, thereby decreasing therapy effectiveness. Pharmaceutical care interventions may increase therapy adherence. Objective: To assess the effect of a proactive pharmaceutical care intervention program, Medication Monitoring and Optimization (MeMO), on therapy discontinuation and adherence with lipid-lowering drugs as well as patients’ satisfaction with the intervention program. Methods: This prospective intervention study included 1002 patients initiating lipid-lowering drug therapy from 9 Dutch community pharmacies. In the intervention group (n = 500), the MeMO program was used, comprising continuous monitoring of patients’ adherence to lipid-lowering drugs and personal counseling with nonadherent patients. The intervention group was compared with a historical reference group (n = 502) receiving usual care. Outcomes were therapy discontinuation and adherence. Results: Discontinuation rates with lipid lowering drugs in the first year after drug initiation were 13.6% for the intervention group and 25.9% in the usual care group; continued but non-adherent use was 3.2% and 7.6% in these groups. Patients in the MeMO program had a decreased risk to discontinue medication of 51% (95% confidence interval: 34%-63%). Results were not affected by potential confounders. Patient satisfaction with MeMO was very high; one quarter of patients mentioned that they only received information about their medication from their pharmacy. Conclusions: Improving adherence to lipid lowering drugs can be achieved by a proactive pharmaceutical care program. Pharmacists can contribute to optimal use of chronic medication, which is likely to reduce healthcare costs.