A probabilistic bias analysis for misclassified categorical exposures, with application to oral anti-hyperglycaemic drugs.

PURPOSE: The effect of drug exposure misclassification generally receives little attention in pharmacoepidemiological research. In this paper, we illustrate a probabilistic bias analysis approach for misclassified categorical exposures and apply it in a database study of oral anti-hyperglycaemic drugs (OADs). METHODS: A cohort study based on the Health Search Database general-practice database was carried out by including 12 640 adult (≥40 years) patients newly treated with OADs during 2003-2010. The proportion of days covered by OADs prescriptions during the first year of follow-up was evaluated for each individual, either by means of the prescribed daily dose or the defined daily dose. The effect of misclassification on hypothetical OAD-outcome association profiles was assessed through the proposed probabilistic bias analysis approach, taking advantage of available exposure validation data. RESULTS: During the first year of follow-up, the average (SD) number of months with OADs available was 7 (4) months and 5 (3) months according to the prescribed daily dose and defined daily dose metrics, respectively. Probabilistic bias analysis results based on validation data suggest that the effect of misclassification is complex, as conventional exposure-outcome association estimates may be of greater or lower magnitude than their misclassification-adjusted values. CONCLUSIONS: Misclassification should be taken into account in database studies on the safety of prescribed medications. To this aim, investigators should take advantage of external exposure validation data in sensitivity analysis approaches such as ours. Copyright © 2016 John Wiley & Sons, Ltd.

Persistence with inhaled corticosteroids reduces the risk of exacerbation among adults with asthma: A real-world investigation.

BACKGROUND AND OBJECTIVE: Real-world evidence suggests that persistence with inhaled corticosteroids (ICS), the mainstay of asthma drug therapy, is generally poor. The effect of persistence with ICS on the risk of asthma exacerbation was addressed in a population-based study. METHODS: The cohort of 2335 beneficiaries of the National Health Service provided by the Italian Region of Lombardy, aged 18-40 years and newly treated with ICS during 2005-2008, was followed from their first ICS dispensation until 2010. Discontinuation of treatment with ICS and starting oral corticosteroid therapy during follow-up were respectively regarded as proxies of poor persistence with asthma medication and asthma exacerbation (outcomes). A proportional hazards model was fitted to identify predictors of ICS discontinuation. Case-crossover and case-case-time-control designs and conditional logistic regressions were used to estimate the association between persistence with ICS and asthma exacerbation. RESULTS: Cumulative incidences of discontinuation were 36%, 57% and 78% at 6 months, 1 year and 5 years, respectively. Predictors of poor persistence were female gender, use of antibiotics during follow-up, absence of use of short-acting beta-agonists prior to and after starting treatment with ICS and starting and maintaining ICS monotherapy during follow-up. The odds ratios of asthma exacerbation (and 95% confidence intervals) associated with ICS exposure during the current period, contrasted with exposure during the reference period, were 0.4 (0.2, 0.9) and 0.3 (0.1, 1.0) from case-crossover and case-case-time-control estimates, respectively. CONCLUSION: Persistence with ICS treatment in adults with asthma reduces the risk of exacerbation in the real-life setting.

Incidence, Predictors, and Clinical Implications of Discontinuing Therapy with Inhaled Long-Acting Bronchodilators among Patients with Chronic Obstructive Pulmonary Disease.

Incidence, predictors and effect of discontinuation of long-acting bronchodilators on the risk of death or hospital admission among adults with Chronic Obstructive Pulmonary Disease (COPD) were assessed in a large population-based prospective study carried out by linking Italian healthcare utilization databases. Specifically, the cohort of 17,490 beneficiaries of the National Health Service in the Italian Region of Lombardy, aged 40 years or older, who started long-acting bronchodilators therapy during 2005-2008 was followed from first dispensation until 2012. During this period, patients who experienced discontinuation of long-acting bronchodilators were identified. Hospitalizations for COPD and deaths for any cause (composite clinical outcome) were also identified during follow-up. A Cox proportional hazards model was fitted to identify predictors of discontinuation. The case-crossover design was used to assess the implications of treatment discontinuation on the clinical outcome risk. Cumulative incidences of discontinuation were, respectively, 67%, 80%, and 92% at 6 months, 1 year, and 5 years since initial treatment. Significant predictors of discontinuation were female gender, younger age, starting treatment with fixed-dose combination of inhaled bronchodilators and corticosteroids, using antibiotics, inhaled long-acting bronchodilators and corticosteroids and not using short-acting bronchodilators, other respiratory drugs and systemic corticosteroids during follow-up. Odds ratios (95% confidence intervals) for the clinical outcome associated with not discontinuing long-acting bronchodilators was 0.64 (0.50 to 0.82). In conclusion, in the real-life setting, discontinuation of inhaled long-acting bronchodilators in adults with COPD is high even after just 6 months, even though persistence to these drugs reduces the risk of severe outcomes.

Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases.

PURPOSE: Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics. METHODS: We have analyzed the role of various antidiabetic drugs on HCC in a nested case-control study using the healthcare utilization databases of the Lombardy Region in Italy. This included 190 diabetic subjects with a hospital discharge reporting a diagnosis of malignant HCC and 3772 diabetic control subjects matched to each case on sex, age, date at cohort entry, and duration of follow-up. RESULTS: Increased risks of HCC were found for use of insulin (odds ratio [OR] = 3.73, 95% confidence interval [CI] 2.52-5.51), sulfonylureas (OR = 1.39, 95%CI 0.98-1.99), and repaglinide (OR = 2.12, 95%CI 1.38-3.26), while a reduced risk was found for use of metformin (OR = 0.57, 95%CI 0.41-0.79). The risk of HCC increased with increasing duration of insulin use (OR = 2.52 for <1 year, 5.41 for 1-2 years, and 6.01 for ≥2 years; p for trend < 0.001), while no clear pattern with duration was observed for sulfonylureas, repaglinide, and metformin. CONCLUSION: Our study supports the evidence that patients with diabetes using metformin, and possibly other antidiabetic drugs that increase insulin sensibility, have a reduced risk of HCC, while those using insulin or drugs that increase circulating insulin, such as insulin secretagogues, have an increased risk. Whether these associations are causal, or influenced by different severity of diabetes and/or possible residual bias or misclassification, is still open to discussion.

Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies.

OBJECTIVE: To conduct a systematic review of observational studies on the risk of acute myocardial infarction (AMI) with use of individual nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A search of Medline (PubMed) for observational studies published from 1990 to 2011 identified 3829 articles; 31 reported relative risk (RR) of AMI with use of individual NSAIDs versus nonuse of NSAIDs. Information abstracted in a standardized form from 25 publications was used for the meta-analysis on 18 independent study populations. RESULTS: Random-effects RR (95% confidence interval (CI)) was lowest for naproxen 1.06 (0.94­1.20), followed by celecoxib 1.12 (1.00­1.24), ibuprofen 1.14 (0.98­1.31), meloxicam 1.25 (1.04­1.49), rofecoxib 1.34 (1.22­1.48), diclofenac 1.38 (1.26­1.52), indometacin 1.40 (1.21­1.62), etodolac 1.55 (1.16­2.06), and etoricoxib 1.97 (1.35­2.89). Heterogeneity between studies was present. For new users, RRs (95% CIs) were for naproxen, 0.85 (0.73­1.00); ibuprofen, 1.20 (0.97­1.48); celecoxib, 1.23 (1.00­1.52); diclofenac, 1.41 (1.08­1.86); and rofecoxib, 1.43 (1.21­1.66).Except for naproxen, higher risk was generally associated with higher doses, as defined in each study, overall and in patients with prior coronary heart disease. Low and high doses of diclofenac and rofecoxib were associated with high risk of AMI, with dose­response relationship for rofecoxib. In patients with prior coronary heart disease, except for naproxen, duration of use ≤3 months was associated with an increased risk of AMI. CONCLUSIONS: Most frequently NSAIDs used in clinical practice, except naproxen, are associated with an increased risk of AMI at high doses or in persons with diagnosed coronary heart disease. For diclofenac and rofecoxib, the risk was increased at low and high doses.

Use of antidepressant serotoninergic medications and cardiac valvulopathy: a nested case-control study in the health improvement network (THIN) database.

AIMS: To quantify the risk of cardiac valvulopathy (CV) associated with the use of antidepressant serotoninergic medications (SMs). METHODS: We conducted a case-control study nested in a cohort of users of antidepressant SMs selected from The Health Improvement Network database. Patients who experienced a CV event during follow-up were cases. Cases were ascertained in a random sample of them. Up to 10 controls were matched to each case by sex, age, month and year of the study entry. Use of antidepressant SMs during follow-up was defined as current (the last prescription for antidepressant SMs occurred in the 2 months before the CV event), recent (in the 2-12 months before the CV event) and past (>12 months before the CV event). We fitted a conditional regression model to estimate the association between use of antidepressant SMs and the risk of CV by means of odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Sensitivity analyses were conducted to test the robustness of our results. RESULTS: The study cohort included 752,945 subjects aged 18-89 years. Throughout follow-up, 1663 cases (incidence rate: 3.4 per 10,000 person-years) of CV were detected and were matched to 16,566 controls. The adjusted OR (95% CI) for current and recent users compared with past users of antidepressant SMs were 1.16 (0.96-1.40) and 1.06 (0.93-1.22), respectively. Consistent effect estimates were obtained when considering cumulative exposure to antidepressant SMs during follow-up. CONCLUSIONS: These results would suggest that exposure to antidepressant SMs is not associated with an increased risk of CV.

Issues concerning the use of hormone replacement therapy and risk of fracture: a population-based, nested case-control study.

AIMS: To investigate the effect of duration, how recently it has been used, and age at start of hormone replacement therapy (HRT) and the risk of bone fracture. METHODS: A population-based, nested case-control study was conducted in Lombardia, Northern Italy. The 78,294 women aged 45-75 years who received at least one HRT prescription during 1998-2000 were followed until 2005. Cases were women who experienced bone fracture during follow-up. Up to six controls were randomly selected for each case from the cohort after matching for age and date of cohort entry. The odds ratio of fracture associated with the use of HRT was estimated by conditional logistic regression. RESULTS: One thousand one hundred and seventy-four cases and 6760 controls were included. Compared with women who took HRT for less than 2 months, those who were treated for more than 20 months had an odds ratio (OR) of 0.80 (95% confidence interval 0.65, 0.99). This risk reduction was still significant among current HRT users (OR 0.71, 95% CI 0.55, 0.90) and in women who began therapy at the age of 55-65 years (OR 0.63, 95% CI 0.42, 0.94) or 65-75 years (OR 0.56, 95% CI 0.32, 0.99). There was no statistical evidence of a protective effect for women who had stopped treatment more than 6 months previously or those who began HRT at the age of 45-55 years. CONCLUSIONS: HRT should be continued for long periods to achieve an optimal protection from fracture. The fracture reducing potential of HRT seems to disappear after a few months without treatment and might mainly act in women who begin therapy at older age.

Persistence with oral and transdermal hormone replacement therapy and hospitalisation for cardiovascular outcomes.

BACKGROUND: The effect of persistence with transdermal and oral administrations of hormone replacement therapy (HRT) on the risk of hospitalisation for cardiovascular disease, and the role of income as potential confounder, were explored in a large population-based cohort study. METHODS: Seventy-eight thousand eight hundred and seventy-five women resident in the Italian Lombardy Region aged 45-65 years who received at least one HRT prescription during 1998-2000 were followed until December 2003. The 828 cohort members who experienced at least one hospitalisation for a circulatory system disease were identified from the Regional hospital discharge database. The Regional prescription drug database was used to assess cumulative persistence with hormone treatment during follow-up. Data on individual taxable income was also obtained for women resident in the city of Milan. A proportional hazards model was fitted to estimate the association between cumulative time-dependent persistence with HRT and cardiovascular risk. RESULTS: Compared with women who took HRT for less than 6 months, those exposed for more than 3 years to HRT as a whole, and to transdermal and oral HRT, respectively, showed hazard ratios of 0.65 (95% confidence interval: 0.45, 0.92), 0.53 (0.34, 0.82), and 1.15 (0.47, 2.79). CVD reducing potential of HRT disappeared when estimates were adjusted for income being hazard ratio associated with long-term use 0.94 (0.52, 1.71). CONCLUSIONS: Evidence that CVD risk associated with long-term hormone treatment varies according to the route of HRT administration, and that economic position confounds the effect of HRT on the risk of cardiovascular hospitalisation, is provided by the current study.

Metformin, other antidiabetic drugs, and endometrial cancer risk: a nested case-control study within Italian healthcare utilization databases.

Metformin may reduce the risk of endometrial cancer whereas other drugs for the treatment of type 2 diabetes mellitus appear to increase it, although the evidence is still limited. We investigated this issue using data from a nested case-control study within the healthcare utilization databases of the Lombardy Region, Italy. This study included 376 diabetic women with endometrial cancer and 7485 diabetic controls matched for cases on age, date at cohort entry, and duration of follow-up. We used conditional logistic regression models to estimate the odds ratio (OR) of endometrial cancer in relation to use of antidiabetic drugs, adjusted for the Charlson's comorbidity index, selected medical conditions, prescription of selected drugs, and concomitant use of other antidiabetic drugs. At cohort entry, no significant associations were observed for metformin [OR=0.99, 95% confidence interval (CI) 0.80-1.23], sulfonylureas (OR=1.14, 95% CI 0.91-1.42), insulin (OR=0.72, 95% CI 0.34-1.56), and other antidiabetic drugs (OR=1.21, 95% CI 0.75-1.95). When we considered use during follow-up, a borderline significant excess risk was found for metformin (OR=1.30, 95% CI 1.00-1.70). However, this estimate decreased to 1.07 (95% CI 0.82-1.41) when taking into account BMI using a Monte Carlo sensitivity analysis. No significant associations were found for sulfonylureas (OR=1.16, 95% CI 0.91-1.47), thiazolidinediones (OR=0.77, 95% CI 0.48-1.24), repaglinide (OR=1.32, 95% CI 0.94-1.87), incretins (OR=1.21, 95% CI 0.63-2.32), and insulin (OR=1.19, 95% CI 0.82-1.71). Our data indicate that metformin, insulin, and other antidiabetic drugs did not meaningfully affect the risk of endometrial cancer.

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study.

OBJECTIVES: To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DESIGN: Nested case-control study. SETTING: Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PARTICIPANTS: Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry). MAIN OUTCOME MEASURE: Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed. RESULTS: Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses. CONCLUSIONS: The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

A validation study of a new classification algorithm to identify rheumatoid arthritis using administrative health databases: case-control and cohort diagnostic accuracy studies. Results from the RECord linkage On Rheumatic Diseases study of the Italian Society for Rheumatology.

OBJECTIVES: To develop and validate a new algorithm to identify patients with rheumatoid arthritis (RA) and estimate disease prevalence using administrative health databases (AHDs) of the Italian Lombardy region. DESIGN: Case-control and cohort diagnostic accuracy study. METHODS: In a randomly selected sample of 827 patients drawn from a tertiary rheumatology centre (training set), clinically validated diagnoses were linked to administrative data including diagnostic codes and drug prescriptions. An algorithm in steps of decreasing specificity was developed and its accuracy assessed calculating sensitivity/specificity, positive predictive value (PPV)/negative predictive value, with corresponding CIs. The algorithm was applied to two validating sets: 106 patients from a secondary rheumatology centre and 6087 participants from the primary care. Alternative algorithms were developed to increase PPV at population level. Crude and adjusted prevalence estimates taking into account algorithm misclassification rates were obtained for the Lombardy region. RESULTS: The algorithms included: RA certification by a rheumatologist, certification for other autoimmune diseases by specialists, RA code in the hospital discharge form, prescription of disease-modifying antirheumatic drugs and oral glucocorticoids. In the training set, a four-step algorithm identified clinically diagnosed RA cases with a sensitivity of 96.3 (95% CI 93.6 to 98.2) and a specificity of 90.3 (87.4 to 92.7). Both external validations showed highly consistent results. More specific algorithms achieved >80% PPV at the population level. The crude RA prevalence in Lombardy was 0.52%, and estimates adjusted for misclassification ranged from 0.31% (95% CI 0.14% to 0.42%) to 0.37% (0.25% to 0.47%). CONCLUSIONS: AHDs are valuable tools for the identification of RA cases at the population level, and allow estimation of disease prevalence and to select retrospective cohorts.

Statins and the risk of diabetes: evidence from a large population-based cohort study.

OBJECTIVE: To investigate the relationship between adherence with statin therapy and the risk of developing diabetes. RESEARCH DESIGN AND METHODS: The cohort comprised 115,709 residents of the Italian Lombardy region who were newly treated with statins during 2003 and 2004. Patients were followed from the index prescription until 2010. During this period, patients who began therapy with an antidiabetic agent or were hospitalized for a main diagnosis of type 2 diabetes were identified (outcome). Adherence was measured by the proportion of days covered (PDC) with statins (exposure). A proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS: During follow-up, 11,154 cohort members experienced the outcome. Compared with patients with very-low adherence (PDC <25%), those with low (26-50%), intermediate (51-75%), and high (≥75%) adherence to statin therapy had HRs (95% CIs) of 1.12 (1.06-1.18), 1.22 (1.14-1.27), and 1.32 (1.26-1.39), respectively. CONCLUSIONS: In a real-world setting, the risk of new-onset diabetes rises as adherence with statin therapy increases. Benefits of statins in reducing cardiovascular events clearly overwhelm the diabetes risk.

Long-term use of statins reduces the risk of hospitalization for dementia.

BACKGROUND: Dementia is a major public health problem because of its high prevalence in elderly individuals, particularly in the growing category of subjects aged 80 years or more. There is accumulating evidence that cholesterol may be implicated in the pathogenesis of dementia, and this has led us to assess the relationship between time spent with statins available and the risk of hospitalization for dementia. METHODS: A population-based, nested case-control study was carried out by including the cohort of 152,729 patients from Lombardy (Italy) aged 40 years or older who were newly treated with statins between 2003 and 2004. Cases were the 1380 patients who experienced hospitalization for dementia disease from initial prescription until 2010. Up to twenty controls were randomly selected for each case. Logistic regression was used to model the risk of dementia associated with the cumulative time during which statins were available. Monte-Carlo and rule-out sensitivity analyses were performed to account for unmeasured confounders. RESULTS: Compared with patients who had very short statins coverage (less than 6 months), those on 7-24, 25-48, and >48 months of coverage respectively had risk reductions of 15% (OR: 0.85; 95% CI: 0.74 to 0.98), 28% (OR: 0.72; 95% CI: 0.61 to 0.85), and 25% (OR: 0.75; 95% CI: 0.61 to 0.94). Simvastatin and atorvastatin were both associated with a reduced risk of dementia, while no similar evidence was observed for fluvastatin and pravastatin. CONCLUSIONS: Long-term use of statins seems effective for the prevention of dementia.

Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project).

BACKGROUND: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. METHODS: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. RESULTS: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4-5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. CONCLUSIONS: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

External adjustment for unmeasured confounders improved drug-outcome association estimates based on health care utilization data.

OBJECTIVES: Health care utilization (HCU) databases are widespread sources of data for pharmacoepidemiologic investigations. Possible confounders are typically not measured in such databases. We show how to assess the impact of confounders in a study aimed at comparing cardiovascular (CV) risk according to drug regimen prescribed at starting antihypertensive therapy, nominally one agent (monotherapy) or a combination of agents in a unique tablet (fixed-dose combination) or in at least two distinct tablets (extemporaneous combination). STUDY DESIGN AND SETTINGS: A nested case-control study was carried out by including the 209,650 patients from Lombardy (Italy) newly treated between 2000 and 2001. Cases were the 10,688 patients who were hospitalized for CV disease until 2007. Three controls were selected for each case. Logistic regression was used to model the CV risk associated with initial therapeutic regimen. A Monte Carlo sensitivity analysis was performed for accounting unmeasured confounders (hypertension severity and chronic disease score) by means of external adjustment with medical record (MR) data. RESULTS: Compared with patients on fixed-dose combination, those on extemporaneous combination or monotherapy, respectively, had CV risk increased to 15% (95% confidence interval [CI]: 3%, 29%) or 17% (95% CI: 8%, 26%). External adjustment did not modify the risk associated with monotherapy. In contrast, the excess of risk associated with extemporaneous combination was annulled when external adjustment was applied. CONCLUSION: MR data can be used to assess confounding bias unmeasured from HCU database. Starting antihypertensive therapy with a combination of agents probably reduces the CV risk with respect to monotherapy, even in the setting of primary prevention.

Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice.

Guidelines recommend a combination of 2 drugs to be used as first-step treatment strategy in high-risk hypertensive individuals to achieve timely blood pressure control and avoid early events. The evidence that this is associated with cardiovascular (CV) benefits compared with initial monotherapy is limited, however. The objective of this study was to assess whether, compared with antihypertensive monotherapy, a combination of antihypertensive drugs provides a greater CV protection in daily clinical practice. A population-based, nested case-control study was carried out by including the cohort of 209 650 patients from Lombardy (Italy) aged 40 to 79 years who were newly treated with antihypertensive drugs between 2000 and 2001. Cases were the 10 688 patients who experienced a hospitalization for CV disease from initial prescription until 2007. Three controls were randomly selected for each case. Logistic regression was used to model the CV risk associated with starting on and/or continuing with combination therapy. A Monte-Carlo sensitivity analysis was performed to account for unmeasured confounders. Patients starting on combination therapy had an 11% CV risk reduction with respect to those starting on monotherapy (95% CI: 5% to 16%). Compared with patients who maintained monotherapy also during follow-up, those who started on combination therapy and kept it along the entire period of observation had 26% reduction of CV risk (95% CI: 15% to 35%). In daily life practice, a combination of antihypertensive drugs is associated with a great reduction of CV risk. The indication for using combination of blood pressure drugs should be broadened.

Better compliance to antihypertensive medications reduces cardiovascular risk.

OBJECTIVE: The effect of compliance with antihypertensive medications on the risk of cardiovascular outcomes in a population without a known history of cardiovascular disease has been addressed by a large population-based prospective, cohort study carried out by linking Italian administrative databases. METHODS: The cohort of 242 594 patients aged 18 years or older, residents in the Italian Lombardy Region, who were newly treated for hypertension during 2000-2001, was followed from index prescription until 2007. During this period patients who experienced a hospitalization for coronary or cerebrovascular disease were identified (outcome). Exposure to antihypertensive drugs from index prescription until the date of hospitalization or censoring was assessed. Proportional hazards models were fitted to assess the association between persistence on and adherence with antihypertensive drug therapy and outcome. Data were adjusted for several covariates. RESULTS: During an average follow-up of 6 years, 12 016 members of the cohort experienced the outcome. Compared with patients who experienced at least one episode of treatment discontinuation, those who continued treatment had a 37% reduced risk of cardiovascular outcomes (95% confidence interval 34-40%). Compared with patients who had very low drug coverage (proportion of days covered ≤ 25%), those at intermediate (from 51 to 75%) and high coverage (>75%) had risk reductions of 20% (16-24%) and 25% (20-29%), respectively. Similar effects were observed when coronary and cerebrovascular events were considered separately. CONCLUSIONS: In the real life setting, fulfillment compliance with antihypertensive medications is effective in the primary prevention of cardiovascular outcomes.

Cost-effectiveness of enhancing adherence to therapy with statins in the setting of primary cardiovascular prevention. Evidence from an empirical approach based on administrative databases.

AIM: To estimate the cost-effectiveness of enhancing adherence to statin therapy across a large population without signs of pre-existing cardiovascular disease. METHODS AND RESULTS: The cohort of 84,262 patients aged 40-79 years, resident in the Italian Lombardia Region, who were newly treated with statins during 2002-2003, was followed from index prescription until 2007. During follow-up the 1397 patients who experienced a hospitalization for ischemic heart disease (IHD) were identified (outcome). Adherence from index prescription until the date of hospitalization or censoring was measured by the proportion of days covered by the therapy with statins (PDC). Cost-effectiveness of enhancing adherence was measured through the incremental cost-effectiveness ratio (ICER). The robustness of findings was tested in a sensitivity analysis. Interventions to increase the average level of adherence from 45% (baseline) to 50% ("soft" intervention) or to 90% ("hard" intervention) reduced the number of patients who experience IHD (from 38.9 to 38.4 or 35.8 events every 10,000 person-year, respectively), and increased the cost for drug therapy (from 1326 to 1452 or 2626 thousand euros every 10,000 person-year, respectively). ICER ranged from 243 (95% CI: 230-259) to 413 (391-439) thousand euros every 10,000 person-year for the soft and hard interventions, respectively. CONCLUSIONS: Interventions aimed at enhancing adherence to statin therapy in the setting of primary cardiovascular prevention might offer important benefits in reducing the risk of cardiovascular outcome, but at a substantial cost.

Management of antihypertensive drugs in three European countries.

OBJECTIVES: To compare rates of treatment discontinuation of and changes in initial antihypertensive drug therapy in the natural setting of treatment dispensation of Italy, Sweden and the Netherlands. METHODS: The cohorts included all the 23 715 (Italy), 20 289 (Sweden), and 5801 (the Netherlands) patients aged 40-70 years who received their first antihypertensive drug prescription from July 1, 2006 to September 30, 2006. Discontinuation was assumed if no antihypertensive drug was issued within 90 days following the end of the latest antihypertensive dispensation. Addition or replacement of the initial medication during the 90-day interval were defined as treatment combination or treatment switching. RESULTS: At 9 months after treatment initiation, the discontinuation rate of any antihypertensive drug was 24%. Compared with Italian patients, the discontinuation rate was significantly lower in Swedish [hazard ratios: 0.52, 95% confidence interval (CI): 0.50-0.54] and Dutch patients (hazard ratio: 0.79, 95% CI: 0.75-0.84). Almost 21 and 16% of patients who started on monotherapy respectively combined with and switched to another antihypertensive drug. Compared with Italian patients, the adjusted hazard rate of combining was lower in Swedish patients (hazard ratio: 0.83, 95% CI: 0.79-0.87). The hazard rate of switching was lower in Swedish and Dutch patients than in Italians (hazard ratios: 0.83, 95% CI: 0.79-0.88 and hazard ratio: 0.77, 95% CI: 0.71-0.84 respectively). CONCLUSION: Management of hypertension is unsatisfactory worldwide due to a very high rate of treatment discontinuation or insufficient use of proper treatment strategies.