The impact of patent expiry on drug prices: insights from the Dutch market.

Background: Currently literature on the impact of patent expiry on drug prices is lacking. Objective: To determine the impact of patent expiration and generic entry on drug prices in the Netherlands. Methods: Prescription and price data from 1999 up to and including December 2016 were collected from two national databases. The overall price ratio of drugs prices up to 48 months after patent expiration was compared to the price in the month before expiry. Sub-analyses were performed to provide insights in generic uptake, length of market exclusivity and price development for originators and generics separately. Results: In total 250 drugs faced patent expiration during the study period. Forty-eight months after patent expiration the median price ratio decreased to 0.59 (IQR = 0.23-0.86) compared to the month prior patent expiry. Major differences in price developments were observed depending on the level of revenue prior to patent expiration and the time of patent expiration with ratios ranging from 0.08 (IQR = 0.07-0.16) to 0.81 (IQR = 0.62-0.97). Prior to patent expiry, the price decreased by 2.3% annually while having market exclusivity for 11.3 years on average. Conclusion: This study showed that the median drug price after patent expiration decreased by 41% after 4 years. The results of this study can be used to provide more reliable estimates on drug prices over its lifecycle and can be implemented in economic evaluations to inform the cost-effectiveness and long-term budget impact of new drugs.

Pharmacological treatment of increased vascular risk and cognitive performance in middle-aged and old persons: six-year observational longitudinal study.

BACKGROUND: Lowering vascular risk is associated with a decrease in the prevalence of cardiovascular disease and dementia. However, it is still unknown whether lowering of vascular risk with pharmacological treatment preserves cognitive performance in general. Therefore, we compared the change in cognitive performance in persons with and without treatment of vascular risk factors. METHODS: In this longitudinal observational study, 256 persons (mean age, 58 years) were treated for increased vascular risk during a mean follow-up period of 5.5 years (treatment group), whereas 1678 persons (mean age, 50 years) did not receive treatment (control group). Cognitive performance was three times measured during follow-up using the Ruff Figural Fluency Test (RFFT) and Visual Association Test (VAT), and calculated as the average of standardized RFFT and VAT score per participant. Because treatment allocation was nonrandomized, additional analyses were performed in demographic and vascular risk-matched samples and adjusted for propensity scores. RESULTS: In the treatment group, mean (SD) cognitive performance changed from - 0.30 (0.80) to - 0.23 (0.80) to 0.02 (0.87), and in control group, from 0.08 (0.77) to 0.24 (0.79) to 0.49 (0.74) at the first, second and third measurement, respectively (ptrend < 0.001). After adjustment for demographics and vascular risk, the change in cognitive performance during follow-up was not statistically significantly different between the treatment and control group: mean estimated difference, - 0.10 (95%CI - 0.21 to 0.01; p = 0.08). Similar results were found in matched samples and after adjustment for propensity score. CONCLUSION: Change in cognitive performance during follow-up was similar in treated and untreated persons. This suggests that lowering vascular risk preserves cognitive performance.

Urinary Calcium Excretion and Risk of Chronic Kidney Disease in the General Population.

INTRODUCTION: High urinary calcium excretion (UCaE) has been shown to lead to accelerated renal function decline in individuals with renal tubular diseases. It is not known whether this association also exists in the general population. Therefore, we investigated whether high UCaE is associated with risk of developing chronic kidney disease (CKD) in community-dwelling subjects. METHODS: Urine samples of 5491 subjects who were free of CKD at baseline and participated in the Prevention of Renal and Vascular End-Stage Disease study (a prospective, observational, general population-based cohort of Dutch men and women aged 28-75 years) were examined for UCaE. UCa concentration was measured in two 24-hour urine samples at baseline (1997-1998) by indirect potentiometry. UCaE was treated as a continuous variable and a categorical variable grouped according to sex-specific quintiles for UCaE. UCaE was compared with de novo development of estimated glomerular filtration rate <60 ml/min per 1.73 m2 and/or albuminuria >30 mg/24 h. RESULTS: Baseline median UCaE was 4.13 mmol/24 h for men and 3.52 mmol/24 h for women. During a median follow-up of 10.3 years, 899 subjects developed CKD. After multivariable adjustment, every 1 mmol/24 h higher baseline UCaE was associated with a 6% lower risk for incident CKD during follow-up (hazard ratio: 0.94 [0.88-0.99], P = 0.02). The association was shown to be significantly nonlinear, with highest risk of CKD in the lowest quintile for UCaE (hazard ratio: 1.28 [0.97-1.68], P = 0.09). There was no association between UCaE and mortality or cardiovascular health during follow-up, suggesting that this association was not a reflection of poor nutritional intake due to bad health. DISCUSSION: These findings indicate that high UCaE does not increase risk of CKD, but rather that low UCaE may be harmful.

Prevalence and Effects of Functional Vitamin K Insufficiency: The PREVEND Study.

Matrix Gla Protein (MGP) is a strong vitamin K-dependent inhibitor of soft tissue calcification. We assessed the prevalence of functional vitamin K insufficiency, as derived from plasma desphospho-uncarboxylated MGP (dp-ucMGP), and investigated whether plasma dp-ucMGP is associated with all-cause and cardiovascular mortality in a large general population-based cohort. We included 4275 subjects (aged 53 ± 12 years, 46.0% male) participating in the prospective general population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. The prevalence of functional vitamin K insufficiency (i.e., dp-ucMGP > 500 pmol/L) was 31% in the total study population. This prevalence was significantly higher among elderly and subjects with comorbidities like hypertension, type 2 diabetes, chronic kidney disease, and cardiovascular disease (~50%). After 10 years of follow-up, 279 subjects had died, with 74 deaths attributable to cardiovascular causes. We found significant J-shaped associations of plasma dp-ucMGP with all-cause (linear term: hazard ratio (HR) (95% confidence interval (CI)) = 0.20 (0.12-0.33), p < 0.001; squared term: 1.14 (1.10-1.17), p < 0.001) and cardiovascular mortality (linear term: 0.12 (0.05-0.27), p < 0.001; squared term: 1.17 (1.11-1.23), p < 0.001). These associations remained significant after adjustment for potential confounders. Whether the correction of vitamin K insufficiency improves health outcomes needs to be addressed in future prospective intervention studies.

Screening for elevated albuminuria and subsequently hypertension identifies subjects in which treatment may be warranted to prevent renal function decline.

Background: We investigated whether initial population screening for elevated albuminuria with subsequent screening for hypertension in case albuminuria is elevated may be of help to identify subjects at risk for accelerated decline in kidney function. Methods: We included subjects who participate in the PREVEND observational, general population-based cohort study and had two or more glomerular filtration rate (eGFR) measurements available during follow-up. Elevated albuminuria was defined as an albumin concentration ≥20 mg/L in a first morning urine sample confirmed by an albumin excretion ≥30 mg/day in two 24-h urines. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or use of blood pressure-lowering drugs. eGFR was estimated with the CKD-EPI creatinine-cystatin C equation. Results: Overall, 6471 subjects were included with a median of 4 [95% confidence interval (CI) 2-5] eGFR measurements during a follow-up of 11.3 (95% CI 4.0-13.7) years. Decline in eGFR was greater in the subgroups with elevated albuminuria. This held true, not only in subjects with known hypertension (-1.84 ± 2.27 versus -1.16 ± 1.45 mL/min/1.73 m 2 per year, P < 0.05), but also in subjects with newly diagnosed hypertension (-1.59 ± 1.55 versus -1.14 ± 1.38 mL/min/1.73 m 2 per year, P < 0.05) and in subjects with normal blood pressure (-1.18 ± 1.85 versus -0.81 ± 1.02 mL/min/1.73 m 2 per year in subjects, P < 0.05). This effect was most pronounced in the population ≥55 years of age and male subjects. In addition, subjects with elevated albuminuria had higher blood pressure than subjects with normoalbuminuria, and in subjects with elevated albuminuria as yet undiagnosed hypertension was twice as prevalent as diagnosed hypertension. Conclusions: Initial screening for elevated albuminuria followed by screening for hypertension may help to detect subjects with increased risk for a steeper decline in kidney function.

The association of albuminuria and high-sensitivity C-reactive protein with the efficacy of HMG-coenzyme A reductase inhibitors for cardiovascular event prevention.

BACKGROUND: It is not clear which hypercholesterolemic patients benefit most from ß-hydroxy-ß-methylglutaryl coenzyme A reductase inhibitors with respect to the prevention of cardiovascular events. Early signs of atherosclerotic vascular damage may identify high-risk patients. DESIGN: We studied whether subjects with hypercholesterolemia will benefit more from starting statin treatment in the case of high albuminuria and/or high-sensitivity C-reactive protein (hsCRP). METHODS: Included were subjects who had hypercholesterolemia at baseline, a negative cardiovascular disease history and who were not treated with statins. In total, 2011 subjects were analysed, of whom 695 started with a statin during a follow-up of 7.0 ± 1.7 years. Adjusted hazard ratios (HRs) for cardiovascular events were calculated in subjects who started versus those who did not start a statin stratified for albuminuria less than or ≥ 15 mg/day and/or hsCRP less than or ≥ 3 mg/L. RESULTS: The start of a statin was associated with a beneficial effect on cardiovascular risk in subjects with high albuminuria (HR 0.38 (0.23-0.60)), while the effect of starting a statin was non-significant in subjects with low albuminuria (HR 0.74 (0.44-1.24), P for interaction < 0.05). The effect of starting a statin was similar in subgroups with high and low hsCRP (P for interaction 0.34). When combining albuminuria and hsCRP subgroups, the start of statin treatment was associated with a lower risk of cardiovascular events dependent on albuminuria and not on the hsCRP level. CONCLUSIONS: The start of statin treatment is associated with a significantly lower absolute as well as relative risk of cardiovascular events in subjects with hypercholesterolemia and elevated albuminuria, whereas these drugs had less effect in subjects with normal albuminuria.

Statin use and cognitive function: population-based observational study with long-term follow-up.

We aimed to evaluate the association between statin use and cognitive function. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; low performance, 0-10; high performance, 11-12 points) in an observational study that included 4,095 community-dwelling participants aged 35-82 years. Data on statin use were obtained from a computerized pharmacy database. Analysis were done for the total cohort and subsamples matched on cardiovascular risk (N = 1232) or propensity score for statin use (N = 3609). We found that a total of 904 participants (10%) used a statin. Statin users were older than non-users: mean age (SD) 61 (10) vs. 52 (11) years (p < 0.001). The median duration of statin use was 3.8 (interquartile range, 1.6-4.5) years. Unadjusted, statin users had worse cognitive performance than non-users. The mean RFFT score (SD) in statin users and non-users was 58 (23) and 72 (26) points, respectively (p < 0.001). VAT performance was high in 261 (29%) statin users and 1351 (43%) non-users (p < 0.001). However, multiple regression analysis did not show a significant association of RFFT score with statin use (B, -0.82; 95%CI, -2.77 to 1.14; p = 0.41) nor with statin solubility, statin dose or duration of statin use. Statin users with high doses or long-term use had similar cognitive performance as non-users. This was found in persons with low as well as high cardiovascular risk, and in younger as well as older subjects. Also, the mean RFFT score per quintile of propensity score for statin use was comparable for statin users and non-users. Similar results were found for the VAT score as outcome measure. In conclusion, statin use was not associated with cognitive function. This was independent of statin dose or duration of statin use.

Statin use and cognitive function: population-based observational study with long-term follow-up.

We aimed to evaluate the association between statin use and cognitive function. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; low performance, 0-10; high performance, 11-12 points) in an observational study that included 4,095 community-dwelling participants aged 35-82 years. Data on statin use were obtained from a computerized pharmacy database. Analysis were done for the total cohort and subsamples matched on cardiovascular risk (N = 1232) or propensity score for statin use (N = 3609). We found that a total of 904 participants (10%) used a statin. Statin users were older than non-users: mean age (SD) 61 (10) vs. 52 (11) years (p<0.001). The median duration of statin use was 3.8 (interquartile range, 1.6-4.5) years. Unadjusted, statin users had worse cognitive performance than non-users. The mean RFFT score (SD) in statin users and non-users was 58 (23) and 72 (26) points, respectively (p<0.001). VAT performance was high in 261 (29%) statin users and 1351 (43%) non-users (p<0.001). However, multiple regression analysis did not show a significant association of RFFT score with statin use (B, -0.82; 95%CI, -2.77 to 1.14; p = 0.41) nor with statin solubility, statin dose or duration of statin use. Statin users with high doses or long-term use had similar cognitive performance as non-users. This was found in persons with low as well as high cardiovascular risk, and in younger as well as older subjects. Also, the mean RFFT score per quintile of propensity score for statin use was comparable for statin users and non-users. Similar results were found for the VAT score as outcome measure. In conclusion, statin use was not associated with cognitive function. This was independent of statin dose or duration of statin use.

24 h urinary free cortisol in large-scale epidemiological studies: short-term and long-term stability and sources of variability.

BACKGROUND: Function of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with several somatic and psychiatric health problems. The amount of free cortisol excreted in the urine during 24h (24-h UFC) has often been used as a proxy for HPA-axis function. Reference values for 24-h UFC and their stability in the short and long term, as well as sources of variability, are largely lacking. METHODS: This study was performed in a general population cohort. Participants collected 24-h UFC on two consecutive days (T1), and repeated this collection approximately 2 years later (T2). Cortisol in urine was measured using LC-MS/MS. Height and weight were measured at the research facilities; glomerular filtration rate was estimated using creatinine clearance. Psychological distress (General Health Questionnaire), smoking, alcohol use and exercise were measured by means of questionnaires. RESULTS: 24-h UFC stability on a day-to-day basis was 0.69 (T1, N=1192) and 0.72 (T2, N=963) (both p<0.001). Long-term stability as indicated by correlation between 2-day averages of T1 and T2 was 0.60 (N=972, p<0.001). Multivariable linear regression analysis revealed that 24-h UFC was predicted by urine volume (standardized beta 0.282 (T1, N=1556) and 0.276 (T2, N=1244); both p<0.001) and glomerular filtration rate (standardized beta 0.137 (T1) and 0.179 (T2); both p<0.001), while also sex explained a small part (standardized beta for female sex -0.057 (T1) and -0.080 (T2); both p<0.05). CONCLUSION: 24-h UFC is moderately stable both in the short and the long term. The effects of urine volume and glomerular filtration rate on 24-h UFC are much stronger than those of sex.

Cost-effectiveness of statins for primary prevention in patients newly diagnosed with type 2 diabetes in the Netherlands.

BACKGROUND: Statins are lipid-lowering drugs that reduce the risk of cardiovascular events in patients with diabetes. OBJECTIVES: The objective of this study was to determine whether statin treatment for primary prevention in newly diagnosed type 2 diabetes is cost-effective, taking nonadherence, baseline risk, and age into account. METHODS: A cost-effectiveness analysis was performed by using a Markov model with a time horizon of 10 years. The baseline 10-year cardiovascular risk was estimated in a Dutch population of primary prevention patients with newly diagnosed diabetes from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database, using the United Kingdom Prospective Diabetes Study risk engine. Statin adherence was measured as pill days covered in the IADB.nl pharmacy research database. Cost-effectiveness was measured in costs per quality-adjusted life-year (QALY) from the health care payers' perspective. RESULTS: For an average patient aged 60 years, the base case, statin treatment was highly cost-effective at €2245 per QALY. Favorable cost-effectiveness was robust in sensitivity analysis. Differences in age and 10-year cardiovascular risk showed large differences in cost-effectiveness from almost €100,000 per QALY to almost being cost saving. Treating all patients younger than 45 years at diabetes diagnosis was not cost-effective (weighted cost-effectiveness of almost €60,000 per QALY). CONCLUSIONS: Despite the nonadherence levels observed in actual practice, statin treatment is cost-effective for primary prevention in patients newly diagnosed with type 2 diabetes. Because of large differences in cost-effectiveness according to different risk and age groups, the efficiency of the treatment could be increased by targeting patients with relatively higher cardiovascular risk and higher ages.

Angiotensin-converting enzyme inhibitor treatment and the development of urinary tract infections: a prescription sequence symmetry analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) can reduce urine output, especially when treatment is first started. Since bacterial clearance from the urinary tract is dependent on urine output, it was hypothesized that ACEi may also increase the risk of urinary tract infections (UTIs). OBJECTIVE: Our objective was to assess the risk of UTIs associated with ACEi therapy initiation in the general population. METHODS: A prescription sequence symmetry analysis was performed with the Dutch 'InterAction Database' (IADB.nl) pharmacy prescription database. We selected all patients from the IADB who were incident users of both ACEi and nitrofurantoin (a proxy for UTIs). A relatively short maximum time-span of 4 weeks between both prescriptions was used to limit time-variant confounding. The sequence ratio was calculated by dividing the number of individuals starting ACEi first and nitrofurantoin second by the number of individuals starting nitrofurantoin treatment first and ACEi second. We adjusted for trends in prescribing and estimated 95 % confidence intervals using exact confidence intervals for binomial distributions. To evaluate whether the effect is specific to ACEi and to assess whether the possible mechanism behind an increased risk of UTIs is related to the renin-angiotensin-aldosterone system, we also estimated the risk for ß-adrenoceptor antagonists (ß-blockers). RESULTS: In total, 22,959 incident users of ACEi therapy were eligible for analysis. Of these, 161 patients started ACEi therapy within 4 weeks prior to or after nitrofurantoin therapy initiation. A total of 101 (63 %) started ACEi therapy first followed by nitrofurantoin treatment, while 60 (37 %) patients started nitrofurantoin treatment first, which corresponds to a statistically significant adjusted sequence ratio (ASR) of 1.68 (95 % CI 1.21-2.36). No association was found between ß-blockers and UTI treatment (ASR 1.01, 95 % CI 0.74-1.38). CONCLUSIONS: A significant excess of patients received UTI medication prescriptions following the first month after ACEi initiation. This prescription sequence asymmetry suggests that ACEi initiation increases the risk of developing UTIs.

The population-based prescription database IADB.nl: its development, usefulness in outcomes research and challenges.

Research databases with large numbers of prescriptions in observational settings can provide valuable information in addition to the initial randomized controlled trials. This paper reports on the development of prescription database IADB, formerly known as InterAction Database. IADB contains prescriptions from 54 community pharmacies in The Netherlands and covers a population of 500,000 people. Both the age distribution and the prevalence of drugs used are comparable to a large extent with the Dutch population. The representativeness of the population covered is examined by comparing population composition and drug use with data of the whole Dutch population. Enriching IADB with, among others, clinical parameters by linking to other databases is explored. A strong and unique aspect of IADB is the possibility to track patients over time, even when they receive their medication from different pharmacies. The authors conclude IADB is a useful tool for pharmacoepidemiological and pharmacoeconomic outcomes research.

The effects of antitussive treatment of ACE inhibitor-induced cough on therapy compliance: a prescription sequence symmetry analysis.

BACKGROUND: A common adverse effect of angiotensin-converting enzyme inhibitors (ACEI) is a persistent dry cough. Physicians and pharmacists who fail to recognise dry cough to be ACEI related may prescribe antitussives, instead of recommended ACEI substitution. OBJECTIVE: The aim of this study was to determine the influence of antitussive treatment of ACEI-induced cough on ACEI therapy compliance. METHODS: Prescription data from community pharmacies between 2000 and 2012 were retrieved from the IADB.nl database (InterAction Database) in The Netherlands. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEI initiation (cases) than the other way around (controls). ACEI therapy compliance was assessed using the proportion of days covered (PDC) method; patients with a PDC of at least 80 % were considered compliant. Compliance was compared between patients receiving antitussives for ACEI-induced cough and patients receiving antitussives for other reasons and patients who did not receive antitussives. RESULTS: A total of 1,898 starters of ACEI and antitussives within a half-year time span were included. A significant excess of patients received antitussives after ACEI initiation compared with before ACEI initiation (1,269 cases vs. 629 controls), yielding a sequence ratio of 2.0 (95 % CI 1.8-2.2). The estimated proportion of patients with ACEI-induced cough receiving antitussives decreased over time: from 20.4 % in 2000-2004 to 8.0 % in 2008-2012. ACEI therapy compliance in patients receiving antitussives due to ACEI initiation was 52.4 %, significantly lower than compliance in control patients receiving antitussives for cough unrelated to ACEI (75.5 %, P < 0.001) and control patients who did not receive antitussives (75.2 %, P < 0.001). CONCLUSIONS: Many patients receive antitussives after ACEI initiation. This suggests that ACEI-induced cough is often either not recognized as being ACEI related or is symptomatically treated. Such prescription behaviour may decrease ACEI therapy compliance.

Effect of pravastatin and fosinopril on recurrent urinary tract infections.

OBJECTIVES: Recurrent urinary tract infections (UTIs) are a problem affecting both women and men. Animal experiments and in vitro studies indicate that statins might prevent recurrent UTIs. We assessed the effects of pravastatin on UTI antibiotic prescribing among adults. METHODS: A post hoc analysis was conducted with data from PREVEND IT, a trial among participants randomized to receive pravastatin, fosinopril or placebo in a 2 × 2 factorial design over 4 years. Trial data were linked to the pharmacy prescription database IADB.nl. The primary outcome was the number of prescriptions with a nitrofuran derivate, a sulphonamide or trimethoprim as a proxy for UTI antibiotic prescribing. Generalized estimating equations were used to estimate the effect on the number of UTI antibiotic prescriptions. Cox regression was used to determine the effect on first and second (recurrent) UTI antibiotic prescriptions. RESULTS: Of the 864 trial participants, 655 were eligible for analysis. During an average follow-up of 3.8 years, 112 (17%) participants received at least one UTI antibiotic prescription. Intention-to-treat analyses showed that pravastatin was associated with a reduced total number of UTI antibiotic prescriptions (relative risk, 0.43; 95% CI, 0.21-0.88) and occurrence of second UTI antibiotic prescriptions [hazard ratio (HR), 0.25; 95% CI, 0.08-0.77]. No significant effect on occurrence of first UTI antibiotic prescriptions was found (HR, 0.83; 95% CI, 0.57-1.20). Fosinopril was associated with an increased occurrence of first UTI antibiotic prescriptions (HR, 1.82; 95% CI, 1.16-2.88). Combination therapy with fosinopril and pravastatin did not significantly influence the number of UTI antibiotic prescriptions. CONCLUSIONS: This study suggests that pravastatin can reduce the occurrence of recurrent UTIs. Larger studies among patients with recurrent UTIs are warranted.

Compliance, persistence, and switching patterns for ACE inhibitors and ARBs.

OBJECTIVES: To investigate compliance, persistence, and switching patterns for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). STUDY DESIGN: Drug-utilization analysis using a large prescription database. METHODS: Prescription data for more than 50,000 incident users of ACE inhibitors or ARBs were collected, cumulating close to 200,000 patient-years of medication use. Incidence, drug dosage, 1-year compliance, long-term persistence, and switching patterns were analyzed. The specific drugs investigated were captopril, enalapril, lisinopril, perindopril, ramipril, and fosinopril (ACE inhibitors), and losartan, valsartan, irbesartan, candesartan, and olmesartan (ARBs). Results were adjusted for age, sex, starting date, and comorbidities. RESULTS: The 1-year compliance (88.3% vs 88.3%, P = .996) and 3-year persistence (81.9% vs 82.4%, P = .197) rates were similar between ACE inhibitors and ARBs. Users of ACE inhibitors more often switched therapy (24.2% vs 13.1%, P <.001), primarily to an ARB. Variations in compliance, persistence, and switching behavior were detected between specific ACE inhibitors, but not between specific ARBs. CONCLUSIONS: Although residual confounding and indication bias cannot be ruled out, this study showed that compliance, persistence, and switching behavior varied between specific ACE inhibitors but not between specific ARBs. These results support prescribing of cheap generic ARBs as opposed to expensive ARBs. Apart from factors leading to therapy switches, compliance and persistence were similar between ACE inhibitors and ARBs.

Association of cognitive function with albuminuria and eGFR in the general population.

BACKGROUND AND OBJECTIVES: Recent studies found different associations of cognitive function with albuminuria or estimated GFR (eGFR). Most studies were limited to the elderly or did not take both renal variables into account. Therefore, this study analyzed the association of cognitive function with albuminuria and eGFR in community-dwelling persons aged 35 to 82 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a cross-sectional study comprising 4095 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Cognitive function, measured with the Ruff Figural Fluency Test (RFFT), was treated as the dependent variable, and albuminuria and eGFR were treated as independent variables. RESULTS: The prevalence of albuminuria <10, 10 to 29, and ≥30 mg/24 h was 54%, 31%, and 15%, respectively. Mean eGFR (± SD) was 79 ± 15 ml/min per 1.73 m(2). Because of interaction between albuminuria and age, analyses were performed per age tertile. After multivariate adjustment, albuminuria ≥ 30 mg/24 h, but not eGFR, was associated with lower RFFT score in the youngest tertile (B -5.3; 95% CI, -0.6 to -9.2; P = 0.05), but not in older tertiles. Moreover, subjects in the youngest tertile with increasing albuminuria (5-15 and >15 mg/24 h) before RFFT measurement had lower mean RFFT scores than subjects with stable albuminuria: mean difference -4.9 (P = 0.3) and -6.7 (P = 0.03), respectively. CONCLUSIONS: In this community-based cohort, elevated albuminuria was associated with worse cognitive function in young but not in old persons. There was no association of eGFR with cognitive function.

Screen-and-treat strategies for albuminuria to prevent cardiovascular and renal disease: cost-effectiveness of nationwide and targeted interventions based on analysis of cohort data from the Netherlands.

BACKGROUND: Albuminuria is a marker for renal and cardiovascular (CV) risk, allowing early diagnosis of subjects with elevated renal and CV risk. OBJECTIVE: This study aimed to estimate the cost-effectiveness and budget impact of various population-based screen-and-treat scenarios for elevated albuminuria levels (ie, microalbuminuria) in the Netherlands. METHODS: A multistate transition Markov model was developed to simulate the natural course of albuminuria-based disease progression to dialysis and occurrence of CV events. Several population-based strategies directed at screening for elevated albuminuria were evaluated. These strategies depended on urinary albumin concentration (UAC), urinary albumin excretion (UAE), and age. Transition probabilities were derived from the observational community-based Prevention of Renal and Vascular End Stage Disease (PREVEND) cohort study. Health care costs (in year-2008 euros) and life-years gained were calculated over an 8-year period. In the base-case analysis, we analyzed screening for and treatment of microalbuminuria. Screening for microalbuminuria involved prescreening for UAC >or=20 mg/L, followed by a confirmation test for UAE >or=30 mg/d. Other options based on combinations of albuminuria for UAC prescreening (no prescreening, and >or=10, >or=20, >or=100, and >or=200 mg/L) and UAE confirmation test (>or=15, >or=30, and >or=300 mg/d) for treatment were investigated in scenario analyses. Furthermore, these various strategies based on UAC and UAE values were analyzed in different subgroups based on age (all ages, aged >or=50 years, and aged >or=60 years). RESULTS: The PREVEND study included 8592 Dutch residents aged 28 to 75 years at the time of initial screening. Among a hypothetical cohort of 1000 subjects identified and treated in the base-case analysis, it was estimated (based on PREVEND follow-up data) that, in the screening/treatment and no-screening scenarios, 76 versus 124 CV events occurred, 16 versus 27 CV deaths, and 3 versus 5 dialysis cases, respectively. The per-person difference in net costs for screening was calculated at euro926 (euro2003 vs euro1077), and prevention of CV deaths was estimated to gain 0.0421 discounted life-year per person. Correspondingly, the cost-effectiveness was estimated at euro22,000 per life-year gained. In the base-case analysis, probabilistic sensitivity analysis indicated that the likelihood of cost-effectiveness of a screen-and-treat strategy was 54%, 90%, and 95% for a maximum acceptable cost-effectiveness threshold of euro20,000, euro50,000, and euro80,000 per life-year gained, respectively. Higher albuminuria thresholds for screening and start of treatment further improved the cost-effectiveness but reduced the overall health gains achieved. Limiting screening to those subjects aged >or=50 and >or=60 years resulted in more favorable cost-effectiveness compared with population-based screening without age restriction. CONCLUSIONS: Our analyses suggest the potentially favorable cost-effectiveness of population-based screening for albuminuria in the general Dutch population. The results offer health care decision-makers new tools for considering actual implementation of such screening.

Results of a retrospective database analysis of drug utilization and costs for treatment of chronic hepatitis B virus infection in the northern Netherlands between 2000 and 2006.

OBJECTIVES: The main aims of this work were to describe patterns of medication use in the treatment of chronic hepatitis B virus (HBV) infection in patients in the northern part of the Netherlands and to compare these practices with established guidelines. In addition, the duration of use and the costs of these treatments were investigated. METHODS: We selected subjects from the University of Groningen's IADB.nl database; by 2006, the database provided information about drug utilization from 55 community pharmacies in the northern Netherlands and included a population of 528,911 individuals, of which 49% were male. Eligible subjects had received >or=1 prescription for drugs used to treat chronic HBV infection (ie, lamivudine, pegylated interferon-alpha2a, pegylated interferon-alpha2b, adefovir, tenofovir, and entecavir) between the years 2000 and 2006. The annual prevalence and cumulative incidence of HBV treatment per 1000 people covered in the database were calculated and stratified by sex. Kaplan-Meier survival analysis was used to analyze the duration of use. Drug costs in the treatment were calculated for all patients or per patient, and by drugs used per subperiod (2000-2003 and 2004-2006). Treatments for hepatitis C virus and HIV were excluded from the analyses. RESULTS: From the database, we identified 59 patients (46 male, 13 female), aged 25 to 60 years, who received >or=1 prescription for a medication to treat chronic HBV infection between 2000 and 2006. The overall prevalence of people using chronic treatments for HBV was between 0.03 and 0.06 per 1000 during the years of the study. The cumulative incidence of treatment was approximately 0.01 per 1000 per year (ranging from a high of 0.021 in 2000 to a low of 0.009 in 2006). When stratified by sex, there were more male than female subjects who received medications for HBV. Lamivudine was the most commonly prescribed drug, followed by adefovir and pegylated interferon-alpha2b. In 2000 and 2001, lamivudine was the only medication prescribed for the treatment of chronic HBV. From 2002 to 2006, the prescription rate for lamivudine dropped from 90% to 61%. In contrast, the prescription rate for adefovir increased from 4% in 2003 to 36% in 2006. Pegylated interferon-alpha2b remained stable at 8% to 11% between 2002 and 2006. Twenty-five percent of patients had stopped HBV treatment by the end of 1 year. Fifty-five percent had stopped by 3 years. Seventy-seven percent of patients received their first HBV prescription from a medical specialist. Per patient, the cost of drug therapy was highest with adefovir. From 2004 to 2006, the cost of adefovir therapy accounted for 49% of total expenditures for the treatment of chronic HBV (equivalent to euro128,037; as of January 2010, euro1.00 = US $1.43). The second and third most expensive drugs were tenofovir and pegylated interferon-alpha2b (euro33,700 and euro33,250, respectively). Costs incurred per patient increased over the years of the study period. CONCLUSIONS: The overall prevalence and cumulative incidence of patients with treatments for chronic HBV were relatively low in the northern part of the Netherlands between 2000 and 2006. The prescribing and utilization patterns were in agreement with international and Dutch guidelines. Given the low numbers of prescriptions, the costs also remained relatively low.

Cost effectiveness of angiotensin receptor blocker monotherapy in patients with hypertension in the Netherlands: a comparative analysis using clinical trial and drug utilization data.

BACKGROUND AND OBJECTIVE: Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs]) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs. METHODS: Cost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan, losartan, valsartan, and irbesartan. BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years, using an international health economics model that was adapted to the Netherlands. Dutch costs (2006 values) and complications derived from the model were discounted at 4% and 1.5%, respectively, and cost effectiveness was expressed in net costs per cardiovascular complication averted. In a drug-utilization study, pharmacy dispensing records were used to evaluate differences between within-trial and daily-practice dosing and related costs for treatment in the Netherlands. RESULTS: After 8 weeks, the trial-based analysis showed that treatment with olmesartan versus losartan, valsartan, and irbesartan resulted in a significantly larger decrease in BP (11.5 vs 8.2, 7.9 and 9.9 mmHg [p < 0.05], respectively) and consequently more complications averted. Cost effectiveness for olmesartan, losartan, valsartan, and irbesartan was estimated at euro39,100, euro77,100, euro70,700, and euro50,900 per cardiovascular complication averted, respectively. The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan, with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs. The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice. On average, losartan, valsartan, and irbesartan were administered at doses above those used in clinical trials, whereas olmesartan was dosed lower than in clinical trials, resulting in relatively lower costs. CONCLUSION: Based on the exact trial data, olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting. However, for definite conclusions to be drawn, this hypothesis-generating study requires confirmation from further prospective studies comparing ARBs based on comparable BP control and including hard endpoints.