To empirically evaluate the concordance of effect estimates between case-only and parallel group ... more To empirically evaluate the concordance of effect estimates between case-only and parallel group designs, and to identify predictors of discrepancies. MEDLINE and EMBASE databases were searched through 31 June 2013. Studies that used both a case-only (case-crossover or self-controlled case-series) and a parallel group design (cohort or case-control) were identified. Spearman correlation coefficient was used to evaluate the concordance between designs. Z-scores were used to assess whether differences in the effect estimates were common, using an absolute threshold value of 1.96. A prediction model was built to identify predictors of discrepancies. The search identified 1,367 articles of which 53 were included for analysis. In total 519 comparisons were made. The correlation coefficient between case-only versus parallel group studies was 0.64 (p<.001). In 221 of the 519 comparisons (43%) the difference between both study designs was larger than the predetermined threshold. The following predictors of discrepancy were found: intermittent exposure, rare event, acute outcome, length of hazard period, type of case-only design and sample size (c-statistic of 0.783). The concordance between effect estimates of case-only and parallel group designs is moderate. Such discrepancies could be predicted by failure to meet assumptions of case-only designs.
In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the... more In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These actions were taken approximately 10 years after the introduction of rosiglitazone, because rosiglitazone might be associated with an increased risk of ischemic heart disease.
Objectives: Recurrent urinary tract infections (UTIs) are a problem affecting both women and men.... more 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.
Additional Supporting Information may be found in the online version of this article at the publi... more Additional Supporting Information may be found in the online version of this article at the publisher's web-site:
Poor quality of reporting of confounding has been observed in observational studies prior the STr... more Poor quality of reporting of confounding has been observed in observational studies prior the STrenghtening the Reporting of Observational studies in Epidemiology (STROBE) statement, a reporting guideline for observational studies. We assessed whether the reporting of confounding improved after the STROBE statement. We searched MEDLINE for all articles about observational cohort and case-control studies on interventions with a hypothesized beneficial effect in five general medical and five epidemiologic journals published between January 2010 and December 2012. We abstracted data for the baseline period before the publication of the STROBE statement (January 2004-April 2007) from a prior study. Six relevant items related to confounding were scored for each article. A comparison of the median number of items reported in both periods was made. In total, 174 articles published before and 220 articles published after the STROBE statement were included. The median number reported items was similar before and after the publication of the STROBE statement [median, 4; interquartile range [IQR], 3-5 vs. median, 4; IQR, 3.75-5]. However, the distribution of the number of reported items shifted somewhat to the right (P = 0.01). Although the quality of reporting of confounding improved in certain aspects, the overall quality remains suboptimal.
Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, ... more Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, mortality and health-care utilization in the elderly population. A theoretical model was built to assess the levels of vaccine effectiveness and vaccine costs for which a hypothetical RSV-vaccine for Dutch elderly could be cost-effective. Different vaccination strategies were evaluated by changing the levels of vaccine effectiveness and the willingness to pay per quality-adjusted life year gained (QALY). Outcome measures included direct medical costs, QALYs, life years gained, incremental cost-effectiveness ratios (ICERs) and the maximum total vaccination costs per individual (i.e. (vaccine price+administration costs)×nr of doses) while remaining cost-effective. Using base-case assumptions, it was estimated that vaccination of all persons 60 years and older would prevent 3402GP visits, 2989 antibiotic prescriptions, 535 hospitalizations and 249 deaths and would cost €73,261 per QALY, for...
Background: In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was in... more Background: 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.
Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease... more Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands. Therefore, we re-assessed the potential incremental cost-effectiveness ratio (ICER) of vaccinating infants in the Netherlands with a MenB vaccine. Routine infant vaccination (2, 3, 4+11 mo) could prevent 39 cases of MenB disease in a single birth cohort, corresponding to a total gain of 133 quality-adjusted life years (QALYs). However, this strategy is unlikely to be cost-effective if the vaccine costs €40 per dose (€243,778 per QALY). At a disease incidence of 5.7 per 100,000 person-years or a vaccine price of €10 per dose including administration costs, the ICER becomes more acceptable and remains below a threshold of €50,000 per QALY. A cohort of 185,000 Dutch newborns was followed in a Markov model to compare routine vaccination against MenB disease with no vaccination. The ICER was estimated for different disease incidences. The study was performed from a societal perspective. At the current low level of disease incidence, introduction of routine infant vaccination, following a 2, 3, 4+11 mo schedule, against MenB disease is unlikely cost-effective in the Netherlands. If the MenB disease incidence increases or the vaccine price is substantially lower than €40, routine infant vaccination has the potential to be cost-effective.
Each year a substantial number of Dutch elderly suffers from herpes zoster (HZ), caused by the re... more Each year a substantial number of Dutch elderly suffers from herpes zoster (HZ), caused by the reactivation of the varicella zoster virus (VZV). A potential complication of HZ is postherpetic neuralgia (PHN) which results in a prolonged loss of quality of life. A large randomized clinical trial, labelled the Shingles Prevention study (SPS), demonstrated that a live attenuated VZV vaccine can reduce the incidence of HZ and PHN. We aimed to estimate the incremental cost-effectiveness ratio (ICER) of vaccination of the elderly against HZ versus no such vaccination in The Netherlands. A cohort model was developed to compare the costs and effects in a vaccinated and a non-vaccinated age- and gender-stratified cohort of immune-competent elderly. Vaccination age was varied from 60 to 75 years. Data from published literature such as the SPS were used for transition probabilities. The study was performed from the societal as well as the health care payer's perspective and results were expressed in euros per quality-adjusted life year (QALY) gained. In the base case, we estimated that vaccination of a cohort of 100,000 60-year-olds would prevent 4136 cases of HZ, 305 cases of PHN resulting in a QALY-gain of 209. From the societal perspective, a total of €1.9 million was saved and the ICER was €35,555 per QALY gained when a vaccine price of €87 was used. Vaccination of women resulted in a lower ICER than vaccination of men (€33,258 vs. €40,984 per QALY gained). The vaccination age with the most favourable ICER was 70 years (€29,664 per QALY gained). Parameters with a major impact on the ICER were the vaccine price and HZ incidence rates. In addition, the model was sensitive to utility of mild pain, vaccine efficacy at the moment of uptake and the duration of protection induced by the vaccine. Vaccination against HZ might be cost-effective for ages ranging from 60 to 75 when a threshold of €50,000 per QALY gained would be used, at €20,000 per QALY this might not be the case. Additional information on the duration of vaccine-protection is needed to further optimize cost-effectiveness estimations.
Patients with diabetes mellitus are at increased risk of developing cardiovascular disease. Contr... more Patients with diabetes mellitus are at increased risk of developing cardiovascular disease. Controlling lipid levels has a preventive effect on the occurrence of major cardiovascular and cerebrovascular events. Individual trials have shown varying data on the efficacy of treatment with lipid-lowering statin therapy in the primary prevention of such events in diabetes. The objective of this study was to assess the efficacy of statins in the primary prevention of the first-time occurrence of a major cardiovascular or cerebrovascular event in diabetic patients. Secondary endpoints were fatal/non-fatal stroke, fatal/non-fatal myocardial infarction and all-cause mortality. A systematic search for trial reports was conducted in PubMed, EMBASE, The Cochrane library and clinicaltrials.gov for the years 1966-2011. Reference lists of reviews and meta-analyses of related subjects were searched. High-quality, randomized, double-blinded clinical trials comparing a statin with placebo for the primary prevention of major cardiovascular and cerebrovascular events in diabetic patients were selected. Only large studies with a minimum of 500 diabetic participants followed-up for at least 2 years were included. Endpoints were major cardiovascular and cerebrovascular events. Trial and patient characteristics were extracted by three researchers. The quality of the included studies was tested with the Jadad score. The combined effect on primary as well as secondary endpoints was measured with a fixed-effect model. Publication bias was examined with a funnel plot. Four trials were included, for a total of 10,187 participants. Treatment with statins in the primary prevention of major cardiovascular and cerebrovascular events in diabetic patients resulted in a significant relative risk (RR) reduction in the first-time occurrence of major cardiovascular or cerebrovascular events (RR 0.75, 95% CI 0.67-0.85), fatal/non-fatal stroke (RR 0.69, 95% CI 0.51-0.92) and fatal/non-fatal myocardial infarction (RR 0.70, 95% CI 0.54-0.90) and a non-significant RR reduction in all-cause mortality (RR 0.84, 95% CI 0.65-1.09). Among the studies there was non-significant heterogeneity in the individual effect estimates and no publication bias. Exclusion criteria and endpoints varied slightly between studies. The type and dosing of statin therapy differed between studies. Non-compliance in the statin treatment group and the use of statin treatment in the placebo group could have led to lower risk reductions. Treatment with statins in primary prevention among diabetic patients has a significant beneficial effect on event rates of the first-time occurrence of a major cardiovascular or cerebrovascular event, fatal/non-fatal stroke and fatal/non-fatal myocardial infarction. There was a non-significant RR reduction in all-cause mortality.
ABSTRACT Angiotensin-converting enzyme inhibitors (ACEi) can reduce urine output, especially when... more ABSTRACT 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). Our objective was to assess the risk of UTIs associated with ACEi therapy initiation in the general population. 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 β-adrenoceptor antagonists (β-blockers). 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 β-blockers and UTI treatment (ASR 1.01, 95 % CI 0.74-1.38). 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.
To empirically evaluate the concordance of effect estimates between case-only and parallel group ... more To empirically evaluate the concordance of effect estimates between case-only and parallel group designs, and to identify predictors of discrepancies. MEDLINE and EMBASE databases were searched through 31 June 2013. Studies that used both a case-only (case-crossover or self-controlled case-series) and a parallel group design (cohort or case-control) were identified. Spearman correlation coefficient was used to evaluate the concordance between designs. Z-scores were used to assess whether differences in the effect estimates were common, using an absolute threshold value of 1.96. A prediction model was built to identify predictors of discrepancies. The search identified 1,367 articles of which 53 were included for analysis. In total 519 comparisons were made. The correlation coefficient between case-only versus parallel group studies was 0.64 (p<.001). In 221 of the 519 comparisons (43%) the difference between both study designs was larger than the predetermined threshold. The following predictors of discrepancy were found: intermittent exposure, rare event, acute outcome, length of hazard period, type of case-only design and sample size (c-statistic of 0.783). The concordance between effect estimates of case-only and parallel group designs is moderate. Such discrepancies could be predicted by failure to meet assumptions of case-only designs.
In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the... more In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These actions were taken approximately 10 years after the introduction of rosiglitazone, because rosiglitazone might be associated with an increased risk of ischemic heart disease.
Objectives: Recurrent urinary tract infections (UTIs) are a problem affecting both women and men.... more 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.
Additional Supporting Information may be found in the online version of this article at the publi... more Additional Supporting Information may be found in the online version of this article at the publisher's web-site:
Poor quality of reporting of confounding has been observed in observational studies prior the STr... more Poor quality of reporting of confounding has been observed in observational studies prior the STrenghtening the Reporting of Observational studies in Epidemiology (STROBE) statement, a reporting guideline for observational studies. We assessed whether the reporting of confounding improved after the STROBE statement. We searched MEDLINE for all articles about observational cohort and case-control studies on interventions with a hypothesized beneficial effect in five general medical and five epidemiologic journals published between January 2010 and December 2012. We abstracted data for the baseline period before the publication of the STROBE statement (January 2004-April 2007) from a prior study. Six relevant items related to confounding were scored for each article. A comparison of the median number of items reported in both periods was made. In total, 174 articles published before and 220 articles published after the STROBE statement were included. The median number reported items was similar before and after the publication of the STROBE statement [median, 4; interquartile range [IQR], 3-5 vs. median, 4; IQR, 3.75-5]. However, the distribution of the number of reported items shifted somewhat to the right (P = 0.01). Although the quality of reporting of confounding improved in certain aspects, the overall quality remains suboptimal.
Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, ... more Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of morbidity, mortality and health-care utilization in the elderly population. A theoretical model was built to assess the levels of vaccine effectiveness and vaccine costs for which a hypothetical RSV-vaccine for Dutch elderly could be cost-effective. Different vaccination strategies were evaluated by changing the levels of vaccine effectiveness and the willingness to pay per quality-adjusted life year gained (QALY). Outcome measures included direct medical costs, QALYs, life years gained, incremental cost-effectiveness ratios (ICERs) and the maximum total vaccination costs per individual (i.e. (vaccine price+administration costs)×nr of doses) while remaining cost-effective. Using base-case assumptions, it was estimated that vaccination of all persons 60 years and older would prevent 3402GP visits, 2989 antibiotic prescriptions, 535 hospitalizations and 249 deaths and would cost €73,261 per QALY, for...
Background: In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was in... more Background: 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.
Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease... more Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands. Therefore, we re-assessed the potential incremental cost-effectiveness ratio (ICER) of vaccinating infants in the Netherlands with a MenB vaccine. Routine infant vaccination (2, 3, 4+11 mo) could prevent 39 cases of MenB disease in a single birth cohort, corresponding to a total gain of 133 quality-adjusted life years (QALYs). However, this strategy is unlikely to be cost-effective if the vaccine costs €40 per dose (€243,778 per QALY). At a disease incidence of 5.7 per 100,000 person-years or a vaccine price of €10 per dose including administration costs, the ICER becomes more acceptable and remains below a threshold of €50,000 per QALY. A cohort of 185,000 Dutch newborns was followed in a Markov model to compare routine vaccination against MenB disease with no vaccination. The ICER was estimated for different disease incidences. The study was performed from a societal perspective. At the current low level of disease incidence, introduction of routine infant vaccination, following a 2, 3, 4+11 mo schedule, against MenB disease is unlikely cost-effective in the Netherlands. If the MenB disease incidence increases or the vaccine price is substantially lower than €40, routine infant vaccination has the potential to be cost-effective.
Each year a substantial number of Dutch elderly suffers from herpes zoster (HZ), caused by the re... more Each year a substantial number of Dutch elderly suffers from herpes zoster (HZ), caused by the reactivation of the varicella zoster virus (VZV). A potential complication of HZ is postherpetic neuralgia (PHN) which results in a prolonged loss of quality of life. A large randomized clinical trial, labelled the Shingles Prevention study (SPS), demonstrated that a live attenuated VZV vaccine can reduce the incidence of HZ and PHN. We aimed to estimate the incremental cost-effectiveness ratio (ICER) of vaccination of the elderly against HZ versus no such vaccination in The Netherlands. A cohort model was developed to compare the costs and effects in a vaccinated and a non-vaccinated age- and gender-stratified cohort of immune-competent elderly. Vaccination age was varied from 60 to 75 years. Data from published literature such as the SPS were used for transition probabilities. The study was performed from the societal as well as the health care payer's perspective and results were expressed in euros per quality-adjusted life year (QALY) gained. In the base case, we estimated that vaccination of a cohort of 100,000 60-year-olds would prevent 4136 cases of HZ, 305 cases of PHN resulting in a QALY-gain of 209. From the societal perspective, a total of €1.9 million was saved and the ICER was €35,555 per QALY gained when a vaccine price of €87 was used. Vaccination of women resulted in a lower ICER than vaccination of men (€33,258 vs. €40,984 per QALY gained). The vaccination age with the most favourable ICER was 70 years (€29,664 per QALY gained). Parameters with a major impact on the ICER were the vaccine price and HZ incidence rates. In addition, the model was sensitive to utility of mild pain, vaccine efficacy at the moment of uptake and the duration of protection induced by the vaccine. Vaccination against HZ might be cost-effective for ages ranging from 60 to 75 when a threshold of €50,000 per QALY gained would be used, at €20,000 per QALY this might not be the case. Additional information on the duration of vaccine-protection is needed to further optimize cost-effectiveness estimations.
Patients with diabetes mellitus are at increased risk of developing cardiovascular disease. Contr... more Patients with diabetes mellitus are at increased risk of developing cardiovascular disease. Controlling lipid levels has a preventive effect on the occurrence of major cardiovascular and cerebrovascular events. Individual trials have shown varying data on the efficacy of treatment with lipid-lowering statin therapy in the primary prevention of such events in diabetes. The objective of this study was to assess the efficacy of statins in the primary prevention of the first-time occurrence of a major cardiovascular or cerebrovascular event in diabetic patients. Secondary endpoints were fatal/non-fatal stroke, fatal/non-fatal myocardial infarction and all-cause mortality. A systematic search for trial reports was conducted in PubMed, EMBASE, The Cochrane library and clinicaltrials.gov for the years 1966-2011. Reference lists of reviews and meta-analyses of related subjects were searched. High-quality, randomized, double-blinded clinical trials comparing a statin with placebo for the primary prevention of major cardiovascular and cerebrovascular events in diabetic patients were selected. Only large studies with a minimum of 500 diabetic participants followed-up for at least 2 years were included. Endpoints were major cardiovascular and cerebrovascular events. Trial and patient characteristics were extracted by three researchers. The quality of the included studies was tested with the Jadad score. The combined effect on primary as well as secondary endpoints was measured with a fixed-effect model. Publication bias was examined with a funnel plot. Four trials were included, for a total of 10,187 participants. Treatment with statins in the primary prevention of major cardiovascular and cerebrovascular events in diabetic patients resulted in a significant relative risk (RR) reduction in the first-time occurrence of major cardiovascular or cerebrovascular events (RR 0.75, 95% CI 0.67-0.85), fatal/non-fatal stroke (RR 0.69, 95% CI 0.51-0.92) and fatal/non-fatal myocardial infarction (RR 0.70, 95% CI 0.54-0.90) and a non-significant RR reduction in all-cause mortality (RR 0.84, 95% CI 0.65-1.09). Among the studies there was non-significant heterogeneity in the individual effect estimates and no publication bias. Exclusion criteria and endpoints varied slightly between studies. The type and dosing of statin therapy differed between studies. Non-compliance in the statin treatment group and the use of statin treatment in the placebo group could have led to lower risk reductions. Treatment with statins in primary prevention among diabetic patients has a significant beneficial effect on event rates of the first-time occurrence of a major cardiovascular or cerebrovascular event, fatal/non-fatal stroke and fatal/non-fatal myocardial infarction. There was a non-significant RR reduction in all-cause mortality.
ABSTRACT Angiotensin-converting enzyme inhibitors (ACEi) can reduce urine output, especially when... more ABSTRACT 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). Our objective was to assess the risk of UTIs associated with ACEi therapy initiation in the general population. 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 β-adrenoceptor antagonists (β-blockers). 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 β-blockers and UTI treatment (ASR 1.01, 95 % CI 0.74-1.38). 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.
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