Luca Merlino

Discontinuation of and changes in drug therapy for hypertension among newly-treated patients: a population-based study in Italy.

Objectives To assess rates and determinants of treatment discontinuation of or changes in initial antihypertensive drug therapy in a large cohort of patients from Lombardia (Italy). Methods The cohort included 445 356 patients aged 40 –80 years who received their first antihypertensive drug prescription (monotherapy) during 1999–2002. Discontinuation was defined by the absence of any antihypertensive prescription during a 90-day period following the end of the latest prescription. If during the same period a drug of a different class was added or replaced the initial prescription, treatment modification was regarded as combination or switching, respectively. Competing risks methodology was used to estimate and compare cause-specific cumulative incidence. Results Cumulative incidences of discontinuation, combination and switching were respectively 33, 14 and 15% at 6 months, 41, 18 and 17% at 1 year, and 50, 25 and 19% at 5 years since initial treatment. Compared with patients starting treatment with angiotensin-converting enzyme inhibitors, the rate of discontinuation was less for patients on angiotensin receptor blockers with a hazard ratio of 0.92 (95% confidence interval =0.90-0.94), whereas increased discontinuation was observed for patients starting with other drugs, mainly β-blockers with a hazard ratio of 1.64 (1.62-1.67); and diuretics with a hazard ratio of 1.83 (1.81-1.85). Conclusion In the general population of Lombardia, discontinuation of the initial single antihypertensive drug treatment is a common phenomenon, whereas switching to another monotherapy and to combination treatment occur at similarly much lower rates. Blockers of the renin-angiotensin system are associated with the lowest incidence of treatment discontinuation.

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.

AIMnTo estimate the cost-effectiveness of enhancing adherence to statin therapy across a large population without signs of pre-existing cardiovascular disease.nnnMETHODS AND RESULTSnThe 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.nnnCONCLUSIONSnInterventions 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.

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

BACKGROUNDnDementia 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.nnnMETHODSnA 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.nnnRESULTSnCompared 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.nnnCONCLUSIONSnLong-term use of statins seems effective for the prevention of dementia.

Discontinuity and failures of therapy with bisphosphonates: joint assessment of predictors with multi-state models.

Data from a cohort of women treated with bisphosphonates were used to illustrate that multi‐state models may be the useful tools of analysis where two causes of treatment failure are the ultimate outcome of interest, and the sequence of recurrent episodes of treatment starting and discontinuing is also of concern.

Cost-effectiveness of enhancing adherence to therapy with blood pressure-lowering drugs in the setting of primary cardiovascular prevention

OBJECTIVEnTo estimate the cost-effectiveness of enhancing adherence to blood pressure (BP)-lowering drug therapy in a large population without signs of preexisting cardiovascular (CV) disease.nnnMETHODSnA cohort of 209,650 patients aged 40 to 79 years resident in the Italian Region of Lombardia and newly treated with BP-lowering drugs during 2000 to 2001 was followed from index prescription to 2007. During the follow-up, the 10,688 patients who experienced a hospitalization for a coronary or cerebrovascular event were identified (outcome). Adherence was measured by the proportion of days covered by the therapy with BP-lowering drugs. The cost-effectiveness of enhancing adherence was measured through the incremental cost-effectiveness ratio.nnnRESULTSnEnhancing adherence from 52% (baseline) to 60% and 80% led to a reduced rate for CV outcomes (from 85 to 83 and 77 events every 10,000 person-year, respectively) and increased the cost for drug therapy (from €1,325k to €1,507k and €1,934k every 10,000 person-year, respectively). The resulting incremental cost-effectiveness ratio decreased from €76k (95% confidence interval €74k-€77k) to €74k (95% confidence interval €72k-€75k) for each CV event avoided by enhancing adherence from baseline to 60% and 80%, respectively.nnnCONCLUSIONSnEnhancing adherence to BP-lowering medications in the setting of primary CV prevention might offer important benefits in reducing the risk of CV outcome, but at a substantial cost.

Respiratory drugs and macrolides prevent asthma exacerbations: A real-world investigation

OBJECTIVEnWe investigated the real-world effectiveness of several drugs (including short- and long-acting beta-agonists [SABAs and LABAs], inhaled corticosteroids [ICS], and antibiotics) in preventing severe asthma exacerbations by carrying-out a large observational study based on the healthcare utilization databases of the Italian Lombardy Region.nnnMETHODSnWe identified all patients aged 6-40 years who performed an Emergency Department visit for asthma during 2010-2012 as cases. To address bias due to unmeasured confounders, we implemented a case-crossover (CC) design. Addressing other specific sources of systematic errors (e.g. protopathic bias) was of particular concern in this study.nnnRESULTSnA total of 7300 cases were included in the study. The CC odds ratios (95% confidence intervals) for current vs. past use were 0.81 (0.71, 0.92) for SABAs, 0.83 (0.72, 0.96) for ICS, 0.78 (0.66, 0.91) for LABA/ICS fixed combinations, 0.79 (0.65, 0.97) for other respiratory drugs, and 0.79 (0.69, 0.92) for macrolides antibiotics. Sensitivity analyses showed that our results were robust with respect to several sources of bias.nnnCONCLUSIONSnOur study provides evidence from the real-world clinical practice on the effectiveness of several respiratory drugs and macrolides in reducing the risk of severe asthma exacerbations.

Early cardiovascular protection by initial two-drug fixed-dose combination treatment vs. monotherapy in hypertension

AimsnGuidelines support use of drug combinations in most hypertensive patients, and recently treatment initiation with two drugs has been also recommended. However, limited evidence is available on whether this leads to greater cardiovascular (CV) protection compared to initial monotherapy.nnnMethods and resultsnUsing the healthcare utilization database of the Lombardy Region (Italy), the 44xa0534 residents of the region (age 40-80 years) who in 2010 started treatment with one antihypertensive drug (nu2009=u200937xa0078) or a two-drug fixed-dose combination (FDC, nu2009=u20097456) were followed for 1 year after treatment initiation to compare the risk of hospitalization for CV disease associated with the two treatment strategies. To limit the confounding associated with non-randomized between-group comparisons, data were also analysed by: (i) matching the two groups by the high-dimensional propensity score (HDPS) and (ii) comparing, in patients experiencing one or more CV events (nu2009=u20092212), the CV event incidence during subperiods in which patients were prescribed mono- or FDC therapy (self-controlled case series design). Compared to initial monotherapy, patients on initial FDC therapy showed a reduced 1 year risk of hospitalization for any CV event (-21%, Pu2009<u20090.01). This was the case also when groups were compared according to the HDPS analysis (-15%, Pu2009<u20090.05). Finally, in patients experiencing CV events, the event incidence was much less when, during the 1 year follow-up, they were under FDC therapy than under monotherapy (-56%, Pu2009<u20090.01). The reduced risk of hospitalization was always significant for ischaemic heart disease and new onset atrial fibrillation, and included hospitalization for cerebrovascular disease and heart failure when monotherapy and FDC therapy were compared within patients.nnnConclusionnIn a real-life setting, a comparison of the incidence of early CV events during antihypertensive monotherapy and FDC shows that the latter strategy leads to a more effective CV protection. This scores in favour of a two-drug FDC strategy as first step in the hypertensive population.

Initial Antihypertensive Treatment Strategies and Therapeutic Inertia.

In many hypertensive patients, treatment is not upgraded despite lack of blood pressure control because of therapeutic inertia. Information is limited, however, on the extent of this phenomenon in real-life medicine. We studied 125u2009635 patients (age 40–85 years) from the Lombardy region (Italy) who started antihypertensive treatment with 1 drug (n=100u2009982) or a 2-drug fixed-dose or free combination (n=24u2009653). A log-binomial regression model was used to estimate the prevalence ratio of combination therapy in relation to the initial treatment strategy. In the initial monotherapy group, patients under drug combinations were 22%, 27%, 32%, and 36% at 6 months, 1, 2, and 3 years later. In the initial combination treatment group, the corresponding percentages were 85%, 82%, 79%, and 78%. This translated into a markedly greater covariate-adjusted propensity of being under a multidrug prescription throughout the follow-up: 3.92 (95% CI, 3.84–4.00) after 6 months and 3.18 (3.12–3.25), 2.56 (2.51–2.60), and 2.23 (2.19–2.27) after 1, 2 and 3 years of treatment. In a propensity score analysis, initial 2-drug combination treatment was also associated with significant reductions in the risk of death (−20%, 11% to 28%) and hospitalization for cardiovascular events (−16%, 10% to 21%) compared with initial monotherapy. Thus, in real life, a large number of patients prescribed initial monotherapy fails to move to combination treatment, as recommended by guidelines. This implies that therapeutic inertia frequently prevents proper treatment uptitration, thereby playing a major role in the low rate of hypertension control that exists worldwide.

Incretin-based drugs and hospitalization for heart failure in the clinical practice: A nested case-control study

BACKGROUND AND AIMSnThere are concerns that incretin-based antidiabetic drugs - including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists - increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting.nnnMETHODS AND RESULTSnWithin a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry. The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83-1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85-1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48-1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses.nnnCONCLUSIONSnThis study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.