Federico Rea

Adherence With Antihypertensive Drug Therapy and the Risk of Heart Failure in Clinical Practice

Randomized clinical trials have shown that antihypertensive treatment reduces the risk of heart failure (HF). Limited evidence exists, however, on whether and to what extent this benefit is translated into real-life practice. A nested case–control study was carried out by including the cohort of 76 017 patients from Lombardy (Italy), aged 40 to 80 years, who were newly treated with antihypertensive drugs during 2005. Cases were the 622 patients who experienced hospitalization for HF from initial prescription until 2012. Up to 5 controls were randomly selected for each case. Logistic regression was used to model the HF risk associated with adherence to antihypertensive drugs, which was measured by the proportion of days covered by treatment (PDC). Data were adjusted for several covariates. Sensitivity analyses were performed to account for possible sources of systematic uncertainty. Compared with patients with very low adherence (PDC, ⩽25%), low, intermediate, and high adherences were associated with progressively lower risk of HF, reduction in the high-adherence group (>75%) being 34% (95% confidence interval, 17%–48%). Similar effects were observed in younger (40–70 years) and older (71–80 years) patients and between patients treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. There was no evidence that adherence with calcium-channel blockers reduced the HF risk. Antihypertensive treatment lowers the HF risk in real-life practice, but adherence to treatment is necessary for a substantial benefit to take place. This is the case with a variety of antihypertensive drugs.

Exposure to statins is associated to fracture risk reduction in elderly people with cardiovascular disease: evidence from the AIFA-I-GrADE observational project

Conflicting findings were observed from clinical trials and observational studies evaluating the association between the use of statins and the risk of fracture. A case–control study nested into a cohort of elderly patients on treatment with statins for cardiovascular secondary prevention was performed on this issue.

Protective effects of antihypertensive treatment in patients aged 85 years or older

Objective: To assess whether in individuals aged 85 years or older, adherence to antihypertensive drugs is accompanied by a reduced risk of cardiovascular events. Methods: A nested case–control study was carried out on a cohort of patients aged 85 years or older, who were newly treated with antihypertensive drugs between 2007 and 2009, using the database available for all citizens (about 10 million) of Lombardy (Italy). Cases were the cohort members who experienced death or hospital discharge for stroke, myocardial infarction (MI) or heart failure from the initial prescription until 2012. Up to five controls were randomly selected for each case. Logistic regression was used to model the outcome risk associated with the adherence with antihypertensive drug therapy. A patient cohort aged 70–84 years was taken for comparison. Results: Compared with patients with very low adherence, those aged 85 years or older (average 88 years) with high adherence showed a risk reduction for death (47%; 95% confidence interval, 5–57%) and all the outcomes combined (34%; 95% confidence interval, 21–45%). The risk of heart failure and stroke was also reduced, whereas the risk of MI was not affected by adherence with antihypertensive drugs. Similar findings were obtained in the cohort of patients aged 70–84 years. Conclusion: Adherence with antihypertensive drug therapy reduced the risk of cardiovascular morbidity in patients aged 85 years or more, the benefit including heart failure and stroke, although not MI, and extending to all-cause death.

One-stage and two-stage meta-analysis of individual participant data led to consistent summarized evidence: lessons learned from combining multiple databases

OBJECTIVE Combining multiple health-care databases (DBs) allows comparing the effects of a wide variety of health-care services. There is a growing interest in methods for combining the results from multiple DBs. We attempted to learn lessons about the performance of one- and two-stage approaches from the reanalysis of data drawn from two studies of pharmacoepidemiology based on multiple DBs. STUDY DESIGN AND SETTING Two nested case-control studies were carried out for estimating the tricyclic antidepressants (TCAs)-arrhythmia and etoricoxib-heart failure associations, respectively, from the Italian Group for Appropriate Drug Prescription in the Elderly and the European Safety of Non-Steroidal Anti-Inflammatory programs. The associations of interest were modeled by conditional logistic regression for matched case-control sets, fitting fixed-effect and random-effect models with both one- and two-stage approaches. RESULTS One- and two-stage approaches gave very similar results, showing uncertainty of TCA-arrhythmia association (random-effect odds ratios [ORs], 95% confidence interval [CI], 1.26, 0.71-2.24, and 1.30, 0.66-2.55, respectively) and statistical evidence for etoricoxib-heart failure association (fixed-effect OR, 95% CI, 1.53, 1.41-1.66, and 1.54, 1.42-1.66, respectively). CONCLUSION Our study offers further evidence that two-stage approach generates estimates very similar as those from one-stage approach, even in the case of between-DB exposure heterogeneity and when several covariates must be concurrently considered. As current rules limit the free movement of electronic health data, our findings open the door of treating data within the country where they are generated and then to apply conventional techniques for summarizing estimates, which is the two-stage approach for meta-analysis using individual participant data.

Clinical value of NT-proBNP assay in the emergency department for the diagnosis of heart failure (HF) in very elderly people

OBJECTIVE Scanty data are available on the accuracy of NT-proBNP in the diagnosis of HF and effects of comorbidities in very elderly patients. METHODS Symptoms, signs, NT-proBNP, eGFR, Ht, CRP and the presence of cardiomegaly and pleuric effusion were assessed in 895 consecutive patients aged 86±4.3 years admitted to Emergency Department and used to define the diagnosis of HF according to Framingham criteria. Receiver operating characteristic curves (ROC) were used to calculate diagnostic performance and cutoff of NT-proBNP. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were computed for all NT-proBNP cutoffs. RESULTS Satisfactory diagnostic performance was obtained with a lower threshold of 980pg/mL (Sn 0.95; NPV 0.90) and a higher threshold of 5340 (Sp 0.85; PPV 0.76) but with 42.4% of patients in the uncertainty area. We determined a second couple of cutoffs (1470-4200) that reduced the gray-area to 27.4%, maintaining an acceptable diagnostic performance compared to commonly used cutoffs (300-1800). Ht, CRP and eGFR all correlated with NT-proBNP in groups with and without HF but none affected diagnostic performance. CONCLUSION NT-proBNP performs satisfactorily for the diagnosis of HF in very elderly patients. Proposed threshold couple, compared with the most used cutoffs, showed a gain in Sp and PPV with a slightly lower performance in Sn and NPV and with a decrease in the gray-area with the second one. Our data do not support the use of different NT-proBNP cutoffs depending on eGFR, Ht and CRP.

Clinical significance of diabetes likely induced by statins: Evidence from a large population-based cohort

AIM To provide information on the extent to which type 2 diabetes more likely induced by statins affects the risk of macrovascular complications compared to diabetes unlikely induced by statins. METHODS The 84,828 residents in the Italian Lombardy Region who were newly treated with statins between 2003 and 2005 were followed from the index statin prescription until 2009 (step-1 follow-up) to identify those starting antidiabetic therapy. The proportion of days of follow-up covered by statins measured adherence with statins. Cohort members who experienced diabetes were 1:3 matched with those who did not developed diabetes for gender, age and previous adherence with statin treatment. The 3321 diabetic - non-diabetic sets, were followed from the initial antidiabetic therapy until 2012 (step-2 follow-up) to estimate the hazard ratio (HR), and 95% Confidence Interval (CI), for macrovascular complications (proportional hazard models) associated with diabetes separately in each category of adherence with statins. RESULTS During the step-1 follow-up, the risk of new-onset diabetes increased progressively with increasing adherence with statins. During the step-2 follow-up, the risk of macrovascular complications associated with diabetes decreased progressively from 1.70 (1.18-2.44), 1.41 (1.17-1.70), 1.30 (1.07-1.57) until 1.10 (0.40-2.80) as adherence with statins during the step-1 follow-up increased. CONCLUSIONS Type 2 diabetes lost its association with increasing macrovascular risk when previous adherence with statins was very high, and thus the chance of its induction by the drug greater. Statin-dependent type 2 diabetes might be prognostically less adverse than diabetes unlikely induced by statins.

Developing and validating a novel multisource comorbidity score from administrative data: a large population-based cohort study from Italy

Objective To develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases. Methods An index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated. Results Primary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily. Conclusion MCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice.

Adherence to Antihypertensive and Cardiovascular Preventive Treatment: The Contribution of the Lombardy Database

This chapter addresses the issue of adherence to cardiovascular prevention therapies, largely based on the analysis of the Lombardy health utilization databases, which include all residents of this region of northern Italy (>10 million). In Italy free or about free health care is provided for all citizens, including antihypertensive, lipid lowering, and antidiabetic drugs upon prescription. This allows to assess adherence from prescription renewal over extended periods. The main results showed that (1) adherence to antihypertensive drug treatment was low with >60% of the patients discontinuing treatment for prolonged periods during the observation time; (2) demographic and clinical factors were involved in this phenomenon which also depended to a pronounced degree on the type of initial treatment, i.e. different monotherapies and drug combinations; (3) similar results were obtained for adherence to statin treatment; and (4) there was a significant positive relationship between reduced adherence to treatment and increased risk of hospitalization for coronary disease, cerebrovascular disease, and heart failure. This was the case in younger and older patients, including those >85 years. Thus, adherence to treatment can substantially modify the beneficial effects of cardiovascular drugs for cardiovascular prevention, as documented by clinical trials. This calls for research approaches that extend the results of trial to their application to medical practice.

HF progression among outpatients with HF in a community setting

BACKGROUND Incidence and prognostic impact of heart failure (HF) progression has been not well addressed. METHODS From 2009 until 2015, consecutive ambulatory HF patients were recruited. HF progression was defined by the presence of at least two of the following criteria: step up of ≥1 New York Heart Association (NYHA) class; decrease LVEF ≥ 10 points; association of diuretics or increase ≥ 50% of furosemide dosage, or HF hospitalization. RESULTS 2528 met study criteria (mean age 76; 42% women). Of these, 48% had ischemic heart disease, 18% patients with LVEF ≤ 35%. During a median follow-up of 2.4 years, overall mortality was 31% (95% CI: 29%-33%), whereas rate of HF progression or death was 57% (95% CI: 55%-59%). The 4-year incidence of HF progression was 39% (95% CI: 37%-41%) whereas the competing mortality rate was 18% (95% CI: 16%-19%). Rates of HF progression and death were higher in HF patients with LVEF ≤ 35% vs >35% (HF progression: 42% vs 38%, p = 0.012; death as a competing risk: 22% vs 17%, p = 0.002). HF progression identified HF patients with a worse survival (HR = 3.16, 95% CI: 2.75-3.72). In cause-specific Cox models, age, previous HF hospitalization, chronic obstructive pulmonary disease, chronic kidney disease, anemia, sex, LVEF ≤ 35% emerged as prognostic factors of HF progression. CONCLUSIONS Among outpatients with HF, at 4 years 39% presented a HF progression, while 18% died before any sign of HF progression. This trend was higher in patients with LVEF ≤ 35%. These findings may have implications for healthcare planning and resource allocation.

Effectiveness of adherence to recommended clinical examinations of diabetic patients in preventing diabetes-related hospitalizations

Objective To validate a set of indicators for quality of diabetes care through their relationship with measurable clinical outcomes. Design A retrospective cohort study was carried out from 2010 to 2015. Setting Population-based study. Data were retrieved from healthcare utilization databases of three Italian regions (Lombardy, Emilia Romagna and Lazio) on the whole covering 20 million citizens. Participants The 77 285 individuals who were newly taken in care for diabetes during 2010 entered into the cohort. Interventions Exposure to selected clinical recommendations (i.e. periodic controls for glycated hemoglobin, lipid profile, urine albumin excretion, serum creatinine and dilated eye exams) was recorded. Main outcomes measures A composite outcome was employed taking into account hospitalizations for brief-term diabetes complications, uncontrolled diabetes, long-term vascular outcomes and no traumatic lower limb amputation. A multivariable proportional hazards model was fitted to estimate hazard ratio, and 95% confidence intervals (CI), for the exposure-outcome association. Results Among the newly taken in care patients with diabetes, those who adhered to almost none (0 or 1), just some (2 or 3) or almost all (4 or 5) recommendations during the first year after diagnosis were 44%, 36% and 20%, respectively. Compared patients who adhered to almost none recommendation, significant risk reductions of 16% (95% CI, 6-24%) and 20% (7-28%) were observed for those who adhered to just some and almost all recommendations, respectively. Conclusions Tight control of patients with diabetes through regular clinical examinations must to be considered the cornerstone of national guidance, national audits and quality improvement incentives schemes.