Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data.

BACKGROUND: Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes. METHODS: In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR). FINDINGS: In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from -0·5% (95% CI -0·7 to -0·3) in Hungary to -4·2% (-4·3 to -4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of -4·2% (95% CI -4·3 to -4·1) in Hong Kong, -4·0% (-4·8 to -3·2) in South Korea, -3·5% (-4·0 to -3·0) in Taiwan, and -3·6% (-4·2 to -2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from -3·0% (95% CI -3·0 to -2·9; US Medicare) to 1·6% (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources. INTERPRETATION: All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes. FUNDING: US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

Peripheral arterial disease: Changes in clinical outcomes and therapeutic strategies in two cohorts, from 2002 to 2008 and from 2008 to 2014. A population-based study.

Background The aim of our study was to evaluate whether treatments for peripheral artery disease changed in two different cohorts identified in 2002 and 2008, and whether this had an impact on mortality and major clinical outcomes after six years of follow-up. Methods Using administrative health databases of the largest region in Northern Italy, we identified patients admitted to hospital for peripheral artery disease in 2002 and 2008. Both cohorts were followed for six years. All cause death, acute coronary syndrome, stroke and major amputations, cardiovascular prevention drugs and revascularization procedures were collected. Incidence of events was plotted using adjusted cumulative incidence function estimates. The risk, for each outcome, was compared between 2002-2008 and 2008-2014 using a multivariable Fine and Gray's semiparametric proportional subdistribution hazards model. Results In 2002 and 2008, 2885 and 2848 patients were identified. Adjusting for age, sex, Charlson comorbidity index and severity of peripheral artery disease we observed a significant reduction (in 2008 vs. 2002) in the risk of acute coronary syndrome (28%), stroke (27%) and major amputation (17%). No change was observed in the risk of death. The percentages of patients with peripheral artery revascularizations, during the hospital stay, increased: 43.8% in 2002 vs. 49.0% in 2008, p < 0.001. From 2002 to 2008 there was a significant absolute increase in the prescription of lipid-lowering drugs (+18%), antiplatelets (+7.2%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (+11.8%), p < 0.001. Conclusions In six years of follow-up we observed a reduction in risk of major cardiovascular events in 2008-2014 in comparison with the 2002-2008 cohort. Increasing use of revascularization interventions and cardiovascular prevention drugs could have contributed to the better prognosis.

Are all people with diabetes and cardiovascular risk factors or microvascular complications at very high risk? Findings from the Risk and Prevention Study.

AIMS: To verify whether it is possible, in people with diabetes mellitus (DM) considered at very high cardiovascular (CV) risk, stratify this risk better and identify significant modifiable risk factor (including lifestyle habits) to help patients and clinicians improve CV prevention. METHODS: People with DM and microvascular diseases or one or more CV risk factors (hypertension, hyperlipidemia, smoking, poor dietary habits, overweight, physical inactivity) included in the Risk and Prevention study were selected. We considered the combined endpoint of non-fatal acute myocardial infarction and stroke and CV death. A multivariate Cox proportional analysis was carried out to identify relevant predictors. We also used the RECPAM method to identify subgroups of patients at higher risk. RESULTS: In our study, the rate of major CV events was lower than expected (5 % in 5 years). Predictors of CV events were age, male, sex, heart failure, previous atherosclerotic disease, atrial fibrillation, insulin treatment, high HbA1c, heart rate and other CV diseases while being physically active was protective. RECPAM analysis indicated that history of atherosclerotic diseases and a low BMI defined worse prognosis (HR 4.51 95 % CI 3.04-6.69). Among subjects with no previous atherosclerotic disease, men with HbA1c more than 8 % were at higher CV risk (HR 2.77; 95 % CI 1.86-4.14) with respect to women. CONCLUSIONS: In this population, the rate of major CV events was lower than expected. This prediction model could help clinicians identify people with DM at higher CV risk and support them in achieving goals of physical activity and HbA1c.

Improving cardiovascular prevention in general practice: Results of a comprehensive personalized strategy in subjects at high risk.

BACKGROUND: Although high cardiovascular risk patients should be the main target of preventive strategies, modifiable risk factors are often inadequately controlled. AIM: To assess feasibility and results of a comprehensive personalized method for cardiovascular prevention in high risk patients followed by their general practitioner. METHODS: Between 2004 and 2007, 12,513 patients (mean age 64.0 ± 9.5 years; 61.5% males) with multiple cardiovascular risk factors or history of atherosclerotic disease were identified and followed for five years. If control of major modifiable cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, smoking, unhealthy diet, physical inactivity) was sub-optimal, at baseline and yearly thereafter general practitioners planned with patients, with the help of a brief checklist, preventive interventions to improve the global risk profile. Main outcome was the control of the seven major modifiable cardiovascular risk factors during follow-up. Secondary outcome was the incidence of cardiovascular deaths and hospitalization for cardiovascular reasons according to the improvement in global cardiovascular risk profile during the first year. RESULTS: Control of all major modifiable risk factors except physical inactivity improved gradually and significantly (p < 0.0001) during follow-up.The improvement in the global cardiovascular risk profile during the first year was independently and significantly associated with a lower rate of major cardiovascular events in the following years (hazard ratio 0.939; 95% confidence interval 0.887-0.994, p = 0.03). CONCLUSIONS: Our comprehensive, personalized method for cardiovascular risk prevention in people at high risk appears feasible in general practice. The improvement in the global cardiovascular risk profile was associated with a better prognosis.

A polypill strategy to improve adherence: results from the FOCUS project.

BACKGROUND: Adherence to evidence-based cardiovascular (CV) medications after an acute myocardial infarction (MI) is low after the first 6 months. The use of fixed-dose combinations (FDC) has been shown to improve treatment adherence and risk factor control. However, no previous randomized trial has analyzed the impact of a polypill strategy on adherence in post-MI patients. OBJECTIVES: The cross-sectional FOCUS (Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention) study (Phase 1) aimed to elucidate factors that interfere with appropriate adherence to CV medications for secondary prevention after an acute MI. Additionally, 695 patients from Phase 1 were randomized into a controlled trial (Phase 2) to test the effect of a polypill (containing aspirin 100 mg, simvastatin 40 mg, and ramipril 2.5, 5, or 10 mg) compared with the 3 drugs given separately on adherence, blood pressure, and low-density lipoprotein cholesterol, as well as safety and tolerability over a period of 9 months of follow-up. METHODS: In Phase 1, a 5-country cohort of 2,118 patients was analyzed. Patients were randomized to either the polypill or 3 drugs separately for Phase 2. Primary endpoint was adherence to the treatment measured at the final visit by the self-reported Morisky-Green questionnaire (MAQ) and pill count (patients had to meet both criteria for adherence at the in-person visit to be considered adherent). RESULTS: In Phase 1, overall CV medication adherence, defined as an MAQ score of 20, was 45.5%. In a multivariable regression model, the risk of being nonadherent (MAQ <20) was associated with younger age, depression, being on a complex medication regimen, poorer health insurance coverage, and a lower level of social support, with consistent findings across countries. In Phase 2, the polypill group showed improved adherence compared with the group receiving separate medications after 9 months of follow-up: 50.8% versus 41% (p = 0.019; intention-to-treat population) and 65.7% versus 55.7% (p = 0.012; per protocol population) when using the primary endpoint, attending the final visit with MAQ = 20 and high pill count (80% to 110%) combined, to assess adherence. Adherence also was higher in the FDC group when measured by MAQ alone (68% vs. 59%, p = 0.049). No treatment difference was found at follow-up in mean systolic blood pressure (129.6 mm Hg vs. 128.6 mm Hg), mean low-density lipoprotein cholesterol levels (89.9 mg/dl vs. 91.7 mg/dl), serious adverse events (23 vs. 21), or death (1, 0.3% in each group). CONCLUSIONS: For secondary prevention following acute MI, younger age, depression, and a complex drug treatment plan are associated with lower medication adherence. Meanwhile, adherence is increased in patients with higher insurance coverage levels and social support. Compared with the 3 drugs given separately, the use of a polypill strategy met the primary endpoint for adherence for secondary prevention following an acute MI. (Fixed Dose Combination Drug [Polypill] for Secondary Cardiovascular Prevention [FOCUS]; NCT01321255).

Drug utilization and polypharmacy in an Italian elderly population: the EPIFARM-elderly project.

OBJECTIVE: To investigate the prescribing patterns and the prevalence of polypharmacy in community-dwelling elderly people, and to analyze the association of chronic medications and number of drug prescriptions with age and sex. METHODS: All prescriptions for people aged 65 years or older reimbursed by the Italian National Health Service (NHS) and dispensed by retail pharmacies of the 15 local health units (LHU) in the Lombardy Region during 2005 were analyzed. Logistic regression analysis was used to assess the association between drug prescription (overall, chronic drugs, and polypharmacy) and age, sex, and LHU of residence. RESULTS: Eighty-eight percent of the 1 ,767 ,239 analyzed elderly received at least one drug prescription. The overall prescription rate was slightly higher for women than men (odds ratio [OR] 1.20; 95%CI 1.19-1.21). Seventy-six percent of the elderly received at least one chronic drug, 46% were exposed to polypharmacy, and 20% to chronic polypharmacy. At multivariate analysis, age and LHU residence of the elderly were the main determinants of drug exposure. A significant correlation was found between the overall prescription prevalence rate and exposure to chronic drugs and to chronic polypharmacy (r(s) = 0.79, p < 0.0005 and r(s) = 0.84, p < 0.0001, respectively). CONCLUSIONS: Our findings indicate that age and LHU residence of the elderly are the main determinants of drug prescribing, and there is evidence of a significant correlation between the overall prescription prevalence rate and exposure to chronic drugs and to chronic polypharmacy.

The 5-HT receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC.

We recently found that intracortical injection of the selective and competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) impaired attentional performance in rats and blockade of 5-hydroxytryptamine (5-HT)2A receptors antagonized this effect. Here, we used the microdialysis technique in conscious rats to study the effect of CPP on extracellular glutamate (GLU) in the medial prefrontal cortex (mPFC) and the regulation of this effect by 5-HT2A receptors. Intraperitoneal injection of 20 mg/kg CPP increased extracellular GLU in the mPFC (201% of basal levels) but had no effect on 5-HT. Intracortical infusion of 100 microm CPP increased extracellular GLU (230% of basal values) and 5-HT (150% of basal values) in the mPFC, whereas 30 microm had no significant effect. The effect of 100 microm CPP on extracellular GLU was abolished by tetrodotoxin, suggesting that neuronal activity is required. Subcutaneous injection of 40 microg/kg M100,907 completely antagonized the effect of 100 microm cpp on extracellular GLU, whereas 10 microg/kg caused only partial attenuation. Likewise, intracortical infusion of 0.1 microm M100,907 completely reversed the increase of extracellular GLU induced by CPP. These findings show that blockade of NMDA receptors in the mPFC is sufficient to increase extracellular GLU locally. The increase of cortical extracellular GLU may contribute to CPP-induced cognitive deficits and blockade of 5-HT2A receptors may provide a molecular mechanism for reversing these deficits caused by dysfunctional glutamatergic transmission in the mPFC.