Is the response to antihypertensive drugs heterogeneous? Rationale for personalized approach.

Arterial hypertension represents the most important cardiovascular risk factor with a direct responsibility for a large share of cardiovascular mortality and morbidity in the world. Despite the wide availability of antihypertensive therapies with documented effectiveness, blood pressure control still remains largely unsatisfactory in large segments of the population. Guidelines for the management of arterial hypertension suggest the preferential use of five classes of drugs-angiotensin-converting enzyme inhibitors, angiotensin II type I receptor inhibitors, calcium channel blockers, thiazide/thiazide-like diuretics, and beta-blockers-recommending the use of combination therapy, preferably in pre-established combinations, for the majority of hypertensive patients. The evidence of a non-negligible heterogeneity in the response to different antihypertensive drugs in different patients suggests the opportunity for personalization of treatment. The notable phenotypic heterogeneity of the population of hypertensive patients in terms of genetic structure, behavioural aspects, exposure to environmental factors, and disease history imposes the need to consider all the potential determinants of the response to a specific pharmacological treatment. The progressive digitalization of healthcare systems is making enormous quantities of data available for machine learning systems which will allow the development of management algorithms for truly personalized antihypertensive therapy in the near future.

Increased nocturnal urinary cortisol levels in the elderly patients with depression, coexisting major geriatric syndromes and combined pathogenetic mechanisms.

BACKGROUND: The mechanisms at the basis of depression are still matter of debate, but several studies in the literature suggest common pathways with dementia (genetic predispositions, metabolic and inflammatory mechanisms, neuropathological changes) and other geriatric syndromes. AIMS: To evaluate the role of cortisol (as marker of the HPA, hypothalamus-pituitary-adrenal axis hyperactivity) in elderly subjects with depressive symptoms (by the means of the AGICO, AGIng and COrtisol, study), in relationship to the presence of the major geriatric syndromes. METHODS: The AGICO study enrolled patients from ten Geriatric Units in Italy. Every subject received a comprehensive geriatric assessment or CGA (including the Mini Mental State Examination or MMSE, Geriatric Depression Scale or GDS and Cornell Scale for Depression in Dementia or CSDD), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal), a CGA-derived frailty index (FI) and a modified measure of allostatic load (AL). RESULTS: The MMSE scores were significantly and inversely related to the values of GDS (p < 0.001) and CSDD (p < 0.05), respectively. The patients with depressive symptoms (GDS/CSDD > 8) showed significantly increased disability, MetS, inflammation, FI and AL and significantly reduced MMSE and renal function. The diurnal and nocturnal urinary cortisol levels in the patients with depressive symptoms (GDS/CSDD > 8) were higher with respects to controls (p < 0.05 for nocturnal difference). DISCUSSION: The AGICO study showed that the stress response is activated in the patients with depression. CONCLUSION: The depression in elderly patient should be reconsidered as a systemic disease, with coexisting major geriatric syndromes (disability, dementia, frailty) and combined pathogenetic mechanisms (metabolic syndrome, impaired renal function, low-grade inflammation, and allostatic load). Cortisol confirmed its role as principal mediator of the aging process in both dementia and metabolic syndrome.

Hyperuricemia increases the risk of cardiovascular mortality associated with very high HdL-cholesterol level.

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.

Reduction of in-hospital non-COVID-19 pneumonia in stroke patients during the COVID-19 pandemic.

BACKGROUND: Measures adopted to contain the spread of SARS-CoV-2 could have led to a reduction in the rate of non-COVID-19 infections. We assessed whether a similar reduction was present in patients with stroke. METHODS: We performed a hospital-based study nested in a prospective population-based registry. We compared prevalence of infections and in-hospital mortality in subjects admitted for acute stroke between the first pandemic year (study period, from March 2020 to February 2021) and the pre-pandemic year (control period, from March 2019 to February 2020). Infections were reported as pneumonia (PNA), urinary tract infections (UTI), and any infection (INF). RESULTS: From the control (n = 677) to the study period (n = 520), the prevalence of INF decreased from 11.5 to 4.6% (p < 0.001) and that of PNA decreased from 6.9 to 2.5% (p = 0.001). No changes in in-hospital mortality and length of hospital stay were observed between the two periods. CONCLUSIONS: The observed reduction of in-hospital pneumonias in patients with stroke was likely attributable to the use of protective measures and limitation of hospital visits. Maintaining some of those measures in the long term may contribute to control infections in hospitalized patients with stroke.

Impact of serum uric acid levels on cardiovascular events and quality of life in patients with chronic coronary syndromes: Insights from a contemporary, prospective, nationwide registry.

BACKGROUND AND AIMS: Hyperuricemia is a metabolic disorder that has been associated with adverse cardiovascular (CV) events. Using the data from a nationwide, prospective registry on patients with chronic coronary syndromes (CCS), we assessed the impact of serum uric acid (SUA) levels on quality of life (QoL) and major adverse CV events (MACE), a composite of CV death and hospitalization for myocardial infarction, heart failure (HF), angina or revascularization at 1-year. METHODS AND RESULTS: Among the 5070 consecutive CCS patients enrolled in the registry, levels of SUA were available for 2394 (47.2%). Patients with SUA levels available at baseline were grouped as low tertile (n = 860; 4.3 [3.7-4.7] mg/dL), middle tertile (n = 739; 5.6 [5.3-5.9] mg/dL) and high tertile (n = 795; 7.1 [6.7-7.9] mg/dL). At 1 year, the incidence of MACE was 3.7%, 4.1% and 6.8% for low, middle and high tertiles, respectively (p = 0.005 for low vs high tertile). Patients in the high tertile of SUA had a significantly higher rate of CV mortality (1.4% vs 0.4%; p = 0.05) and hospital admission for HF (2.8% vs 1.6%; p = 0.03) compared to the low tertile. However, hyperuricemia did not result as an independent predictor of MACE at multivariable analysis [hazard ratio: 1.27; 95% confidence intervals: 0.81-2.00; p = 0.3]. CONCLUSIONS: In this contemporary, large cohort of CCS, those in the high tertile of SUA had a greater burden of CV disease and worse QoL. However, SUA did not significantly influence the higher rate of CV mortality, hospitalization for HF and MACE observed in these patients during 1-year follow-up.

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.

The link between influenza and myocardial infarction: vaccination protects.

The association between influenza and cardiovascular disease has been known since the influenza pandemics of the early years of the last century. This association is more consistent and more lasting in the case of particularly severe infections. Several pathogens, including influenza viruses, can modulate the inflammatory response and influence the biology of atherosclerotic plaque to rupture it and cause a Type 1 myocardial infarction. Clinically relevant viral infections can also exacerbate pre-existing cardiovascular disease and contribute to the development of a Type 2 myocardial infarction through an increase in the metabolic demands of the myocardial tissue for fever and tachycardia and the possible induction of hypoxaemia. Evidence of a relevant protective efficacy of influenza vaccination provides further robust and convincing support for a causal link between influenza and myocardial infarction. Consistent cardiovascular protection linked to influenza vaccination has also been demonstrated in patients with recent myocardial infarction to suggest the possibility that this procedure may become an integral part of in-hospital management of acute coronary syndromes. Despite the solidity of these evidences, acknowledged by the guidelines that recommend influenza vaccination in patients at increased cardiovascular risk, still today an unacceptably high proportion of patients at high cardiovascular risk do not receive flu vaccination. Despite some potential limitations of the current flu vaccination, its advantages in terms of reducing cardiovascular events and related mortality are still such as to justify its wide use, especially, but not limited to, in patients with high cardiovascular risk.

The increased cortisol levels with preserved rhythmicity in aging and its relationship with dementia and metabolic syndrome.

BACKGROUND: In the aging process, the cumulative exposure to stress with increased cortisol levels is considered to be associated to the senescence itself and its related disorders. AIMS: To evaluate the role of cortisol in elderly subjects, with or without dementia, by the means of the AGICO study. METHODS: The AGICO study enrolled patients from ten Geriatric Units in Italy in 2012-2017 (Study Director Prof Paolo Falaschi, S. Andrea Hospital of Rome). Every subject received a comprehensive geriatric assessment (including the Mini-Mental State Examination, MMSE), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal). RESULTS: The MMSE was inversely related to the standardized diurnal and nocturnal urinary cortisol levels (p < 0.025 and p < 0.01, respectively) and the age was positively related (p < 0.01 and p < 0.001, respectively). The ratio between the standardized diurnal and nocturnal urinary cortisol levels was 1.50 ± 1.2 (mean ± standard deviation) and it was not modified by the age or dementia. The standardized diurnal and nocturnal urinary cortisol levels were significantly higher in patients with dementia (MMSE < 24) (p < 0.01). In the analysis of the subgroups with MetS, the highest concentrations of diurnal and nocturnal cortisol were found in patients with both dementia and MetS (p < 0.025 and p < 0.01, respectively). DISCUSSION: The AGICO study showed that the stress response significantly and progressively increases with age. CONCLUSION: The cortisol increase in aging is related to the presence of both dementia and metabolic syndrome.

Insulin resistance and NAFLD may influence memory performance in obese patients with prediabetes or newly-diagnosed type 2 diabetes.

BACKGROUND AND AIMS: Diabetes has consistently been shown to increase risk for cognitive decline. Cognitive deficits may occur at the very earliest stages of diabetes. We sought to estimate the determinants of memory function in a group of middle-aged obese subjects with prediabetes or newly-diagnosed type 2 diabetes mellitus. METHODS AND RESULTS: Sixty-two obese patients in treatment with metformin-with prediabetes (n = 41) or newly diagnosed T2DM (n = 21), were studied. Short- and long-term memory function was assessed through a neuropsychological assessment consisting of two tests and a composite domain z score was calculated. Cardiometabolic variables, such as abdominal MRI quantification of subcutaneous (SAT) and visceral (VAT) adipose tissue content, and of intra-hepatocellular lipid content, as well as insulin sensitivity (Matsuda Index, HOMA-IR) and beta cell performance (Beta Index), by multiple sampling, 8-point oral glucose tolerance test, were also evaluated. Age, non-alcoholic fatty liver disease (NAFLD), and lnHOMA-IR together explained 18% (R square) of the variance in memory domain. Including NAFLD increased the explained variance by 8% and including lnHOMA-IR by 9.1%, whereas the contribution of age and other factors was negligible. CONCLUSION: Preventing and managing insulin resistance in precocious and possibly earlier stages of diabetes might provide benefit in slowering down future cognitive decline.

Correlation between cardiovascular risk factors and cognitive decline.

The number of people suffering from dementia in the world is progressively increasing due to the expansion of the geriatric population in which this clinical condition is more frequent. The appearance of a variable degree of cognitive decline up to full-blown dementia does not, however, represent the inevitable fate of those who age, as the studies conducted in the centenarians clearly indicate. Indeed, the age-specific incidence of dementia has progressively decreased in many geographical areas, probably due to an improvement in lifestyles and health care. In fact, a growing number of scientific evidence shows how chronic exposure over the course of life, starting from young adulthood, to various risk factors-arterial hypertension, diabetes mellitus, obesity, tobacco smoke, sleep disorders-contribute significantly to the development of cognitive decline and dementia in the course of senescence. These risk factors, in fact, can trigger and amplify the various neuropathological mechanisms underlying the development of decline, progressively reducing the functional reserve of the brain. Although definitive evidence deriving from ad hoc intervention studies is not currently available, it is legitimate to assert that the early control of cardiovascular risk factors can represent today the most effective tool for the prevention of dementia.

Neuroprotective activities of bacopa, lycopene, astaxanthin, and vitamin B12 combination on oxidative stress-dependent neuronal death.

Oxidative stress is considered the common effector of the cascade of degenerative events in many neurological conditions. Thus, in this paper we tested different nutraceuticals in H2 O2 in vitro model to understand if could represent an adjuvant treatment for neurological diseases. In this study, nutraceuticals bacopa, lycopene, astaxanthin, and vitamin B12 were used alone or in combination in human neuronal differentiated SH-SY5Y cells upon hydrogen peroxide-induced injury and neuroprotective, neuronal death pathways were analyzed. The nutraceuticals analyzed were able to protect H2 O2 cytotoxic effects, through increasing cell viability and proteins involved in neuroprotection pathways and restoring proteins involved in cell death pathways. On this basis, it is possible to propose the use of these compounds as dietary supplement for the prevention or as adjuvant to the only symptomatic treatments so far available for neurodegenerative diseases.

Neuroprotective potential of choline alfoscerate against ß-amyloid injury: Involvement of neurotrophic signals.

Alzheimer's disease represents the most prevalent neurodegeneration worldwide, clinically characterized by cognitive and memory impairment. New therapeutic approaches are extremely important to counteract this disorder. This research is focused on the potential use of choline alfoscerate in preventing neuronal death using in vitro models of Alzheimer's disease, representing the early stage of the disease, treated before or after the insult with glycerylphosphorylcholine. On the light of the results collected, we can postulate that choline alfoscerate, by the activation of the neurotrophin survival pathway, was able to counteract the detrimental effect of ß-amyloid in both in vitro models, reducing apoptotic cell death and preserving the neuronal morphology.

Is there a relationship between blood pressure values and dementia?

The relationship between arterial hypertension and cognitive decline, two among the conditions with higher prevalence in the elderly population, has gained significant interest, in the scientific community, during the last few years, stemming from the numerous epidemiologic, experimental, and therapeutic evidences suggesting a non-casual correlation between the two conditions. In fact, the brain, for its substantial metabolic and functional complexity, is more susceptible to the harmful effect of high blood pressure than the other target organs. Chronic ischaemic impairment, microvascular damage, and neurodegenerative phenomena are the likely pathophysiologic basis for the correlation between hypertension and cognitive decline. Vascular dementia and Alzheimer's disease, the two prominent forms of senile dementia, seem to represent the end result of the chronic exposure, during the lifetime, to harmful stimuli, among which the most relevant are the cardiovascular risk factors, at least from an epidemiological perspective. Evidences from interventional studies, although limited, seems to support the concept that to limit the spread of senile dementia, the early optimization of the control of cardiovascular risk factors, first and foremost hypertension, is crucial. The occurrence of a variable degree of mental decline, till overt dementia, in the hypertensive patient, represents the final step of a pathophysiologic process that began many years before. There is, then, the clear opportunity to control the pathophysiologic mechanisms leading to cognitive decline in the hypertensive patient.

Nation-wide hypertension screening in Italy: data from May Measurements Month 2017-Europe.

Elevated blood pressure (BP) is a growing burden worldwide, leading to over 10 million deaths each year. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of high BP and to act as a temporary solution to the lack of screening programs worldwide. A similar approach has been used in Italy since 2012, showing inadequate awareness of the consequences of hypertension, a generally increased cardiovascular risk and unsatisfactory BP control in 36% of interviewed individuals. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017, during the joint MMM and World Hypertension Day events. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Screenings were conducted both in cities and villages, indoor and outdoor, by health personnel. Eighty-five sites, involving approximately 300 investigators, took part in MMM17/World Hypertension Day in Italy, screening 10 076 individuals during a month-long period. After multiple imputation, 3099 participants were found (30.8%) to have high BP levels. This was the biggest opportunistic BP screening in a single time-point ever reported in Italy. A significant proportion of individuals had high BP, although it was not possible to differentiate between known treated hypertensive patients with inadequate BP control and as yet undiagnosed hypertensive individuals. Opportunistic screening can reach a significant number of individuals, being a powerful tool for raising awareness and carrying out BP screening.

Neural Stem Cells.

Neural stem cell (NSC) transplantation has provided the basis for the development of potentially powerful new therapeutic cell-based strategies for a broad spectrum of clinical diseases, including stroke, psychiatric illnesses such as fetal alcohol spectrum disorders, and cancer. Here, we discuss pertinent preclinical investigations involving NSCs, including how NSCs can ameliorate these diseases, the current barriers hindering NSC-based treatments, and future directions for NSC research. There are still many translational requirements to overcome before clinical therapeutic applications, such as establishing optimal dosing, route of delivery, and timing regimens and understanding the exact mechanism by which transplanted NSCs lead to enhanced recovery. Such critical lab-to-clinic investigations will be necessary in order to refine NSC-based therapies for debilitating human disorders.

Uric Acid Amplifies Aß Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro.

There is still a considerable debate concerning whether uric acid is neuroprotective or neurotoxic agent. To clarify this topic, we tested the effects of uric acid on neuronal cells biology by using differentiated SHSY5Y neuroblastoma cells incubated with amyloid ß to reproduce an in vitro model of Alzheimer's disease. The incubation of cells with uric acid at the dose of 40 µM or higher significantly reduced cell viability and potentiated the proapoptotic effect of amyloid ß. Finally, uric acid enhanced the generation of 4-hydroxynonenal and the expression of PPARß/δ promoted by amyloid ß, indicating a prooxidant effects. In conclusion, uric acid could exert a detrimental influence on neuronal biology being this influence further potentiated by the concomitant exposure to neurotoxic stimuli. This effect is evident for uric acid concentrations close to those achievable in cerebrospinal fluid in presence of mild hyperuricemia thus suggesting a potential role of uric acid in pathophysiology of cognitive dysfunction. These effects are influenced by the concentrations of uric acid and by the presence of favoring conditions that commonly occur in neurodegenerative disorders and well as in the aging brain, including increased oxidative stress and exposure to amyloid ß. J. Cell. Physiol. 232: 1069-1078, 2017. © 2016 Wiley Periodicals, Inc.

Update on Obesity and Cardiovascular Risk: From Pathophysiology to Clinical Management.

Obesity is an epidemic worldwide. Overweight and multiple obesity-related mechanisms, including dysmetabolic alterations, contribute to cardiovascular deleterious effects. Hence, overweight and obesity have been independently associated with increased cardiovascular risk, whose assessment is crucial for preserving life quality and reducing mortality, and to address appropriate therapeutic strategies in obese patients. Beyond the standard of care in managing overweight and obesity in adults (i.e., diet and physical exercise), several relevant pharmacotherapies have been approved, and several procedures and device types for weight loss have been recommended. In such a contest, medical weight management remains one option for treating excess weight. Most drugs used for obesity reduce appetite and increase satiety and, secondarily, slow gastric emptying to reduce body weight and, therefore, act also to improve metabolic parameters. In this contest, agonists of the glucagon-like peptide-1 receptor (GLP-1RAs) modulate different metabolic pathways associated with glucose metabolism, energy homeostasis, antioxidation, and inflammation. Moreover, this class of drugs has shown efficacy in improving glycemic control, reducing the incidence of cardiovascular events in type 2 diabetic patients, and reducing body weight independently of the presence of diabetes. Recently, in overweight or obese patients with pre-existing cardiovascular disease but without diabetes, the GLP-1RA semaglutide reduced the incidence of cardiovascular and cerebrovascular events and death from cardiovascular causes. Thus, semaglutide has been approved for secondary prevention in obese people with cardiovascular disease. Nevertheless, whether this class of drugs is equally effective for primary prevention in obese people has to be demonstrated. In this review, we will summarize updates on the pathophysiology of obesity, the effects of obesity on cardiovascular risk, the impact of different obesity phenotypes on cardiovascular diseases, and the novelties in the clinical management of obesity for cardiovascular prevention.

Extemporaneous combination therapy with nebivolol/amlodipine for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVE: The investigation of the real-world use of the extemporaneous combination of nebivolol and amlodipine (NA-EXC) in adult patients diagnosed with hypertension in Europe. METHODS: Retrospective analysis of data extracted from seven databases of patient medical records and prescriptions from Italy, Germany, France, Hungary, and Poland, to determine the prevalence and incidence of NA-EXC use and to estimate the number of patients potentially eligible for a single-pill combination of the two antihypertensives. Secondary objectives included: the description of the population of NA-EXC users and the assessment of their adherence to treatment based on the proportion of days covered. RESULTS: The use of NA-EXC was found to be common in Europe and ranged between 2.9% to 9.9% of all patients identified in the databases with a prescription of nebivolol and/or amlodipine. The estimated numbers of patients potentially eligible in 2019 for a single-pill combination of nebivolol and amlodipine in Italy and Germany were, respectively, 178,133 and 113,240. Users of NA-EXC were mostly aged 70-79 years, had metabolic disorders and other comorbidities; >70% of them had received ≥2 concomitant medications before starting NA-EXC. Adherence to NA-EXC was defined as high only in 15.6% to 35% of patients. CONCLUSIONS: The extemporaneous combination of nebivolol and amlodipine is commonly prescribed in Europe, however adherence to the therapy is poor. The development of a single-pill combination of nebivolol and amlodipine may improve adherence by reducing the number of pills administered to patients and thus simplifying treatment regimens.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Extemporaneous combination therapy with nebivolol/ramipril for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVES: To describe the clinical characteristics and treatment adherence in European adult hypertensive patients starting treatment with the extemporaneous combination of nebivolol and ramipril (NR-EXC). METHODS: Retrospective database analysis of patients receiving NR-EXC treatment across five European countries (Italy, Germany, France, Poland, Hungary) over a period ranging from 3 to 9 years (until 30 June 2020) according to data availability for the different data sources. Patient demographics, comorbidities, and treatment adherence were evaluated. RESULTS: We identified 592,472 patients starting NR-EXC. Most of them were over 60 years of age, with ramipril most commonly prescribed at 5 mg (from 30.0 to 57.2% of patients across the databases). Notable comorbidities included diabetes (19.2%) and dyslipidemia (18.2%). The study population was also highly subjected to polytherapy with antithrombotics, lipid-lowering agents, and other lowering blood pressure agents as the most co-prescribed medications, as resulted from Italian database. Up to 59% of the patients did not request a cardiologic visit during the study period. Adherence to therapy was low in 56.3% of the patients, and it was high only in 11.1% of them. CONCLUSIONS: The combination of nebivolol and ramipril is frequently prescribed in Europe, but adherence to treatment is suboptimal. The transition to a single pill combination could enhance treatment adherence and streamline regimens, potentially leading to significant benefits. Improved adherence not only correlates with better blood pressure control but also reduces the risk of cardiovascular events, underscoring the importance of this development.