Federica Nicotra

Individual NSAIDs and Upper Gastrointestinal Complications A Systematic Review and Meta-Analysis of Observational Studies (the SOS Project)

AbstractBackground: 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.

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.

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.

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

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).

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.

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.

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.

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.

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

Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics.

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.