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Background: Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its pathogenesis. Aim: The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach. Materials & methods: We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples. Results: We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10-8). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort. Conclusion: Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension. Original submitted 7 May 2014; Revision submitted 29 July 2014

Chronic kidney disease (CKD) is associated with various consequences to the cardiovascular system and metabolic profile. The classification into stages should be useful for the physician to anticipate and treat early the manifestations of this disease. We have reviewed the current evidence of the potential benefits from screening, monitoring and treating adult patients for CKD stages 1-3 to counter the progression of kidney damage towards end-stage renal disease. In particular, we advocate an integrated vision of kidney and cardiovascular diseases in clinical practice. A Medline/PubMed, Embase and Cochrane Library search from 2001 to 2013 was performed. All articles related to this topic were reviewed. The search strategy was limited to papers on adult patients in English and Italian. The resulting data was organized on the basis of the current guidelines (evidence-based medicine levels of evidence).

Objective: Evaluate the impact of antihypertensive drugs (AHD) on stroke and acute myocardial infarction (AMI) and death for 3 cohorts of patients: diabetics, high risk, and hypertensive. Methods: This was a retrospective cohort obervational study based on administrative database of 7 Italian Local Health Units. Newly treated patients with AHD were enrolled from 01/01/2004 to 06/30/2007. Drug utilization and incidence of death, stroke and AMI were measured until 12/31/2007. Results: The study enrolled 125,770 patients aged ≥ 18-year-old: 8516 diabetic, 8549 high risk, and 108,705 hypertensive. Diabetic and high risk patients were more frequently male (57.2%, 64.9% VS 46.6%) and older (66.4 ± 11.6, 67.5 ± 13.2 VS 61.6 ± 13.9) than hypertensive patients and were more treated with concomitant therapy. Drugs acting on the renin-angiotensin system were the more fre- quent choice in the three cohorts but with a dif- ferent prevalence (63.9%, 52.9%, 35.9% in dia- betic, hypertensive and high risk patients re- spectively). Adherent patients to AHD > 80% were 44.0% among diabetic patients, 48.4% among high risk, 35.2% among hypertensive. A Cox regression model showed that the risk of the combined outcome was determined by increasing age, male gender, presence of concomitant therapy, low adherence to AHD and first choice of AHD. Conclusions: An integrated analysis of prescription and hospital admission database has the great advantage that it uses routinely available data, it can be done quickly and by few staff, and it is less expensive than planned large scale survey.

Objective The present study investigated the effects of switching to different products of the same off-patent active substance (brand name or generic) on therapy discontinuation or substitution with another molecule of the same class, in patients with cardiovascular disease treated with statins and antihypertensives in a ‘real-world’ setting. Design A retrospective cohort study in a ‘real-world’ setting. Setting Analysis of data performed by integrating administrative databases that included approximately two million individuals who are assisted by the National Health System from three Local Health Units located in three different regions of Italy. Participants All patients aged ≥18 years with at least one prescription of simvastatin, ramipril or amlodipine in the period 1 January to 31 December 2010 were included and followed up for 2 years. Main outcome measures Prescription refills occurring during follow-up were evaluated. Frequency of discontinuation of therapy or substitution with another molecule of the same class (eg, from simvastatin to a different statin) during follow-up was identified. Results During follow-up, therapy discontinuation or substitution was found to be more frequent in patients switching to a different product of the same active substance compared with non-switching patients (11.5% vs 10.8% and 22.2% vs 20.8% (p=0.002), respectively, in the simvastatin group; 4.0% vs 3.5% and 24.6% vs 22.7% (p

Hypertension constitutes a significant disease burden to the society, both in terms of the health-related repercussions as well as financial costs incurred due to morbidity and the cumulative cost of drug therapy. In the real world, it would be useful to have the opportunity to consider the appropriate use of antihypertensive drugs to inform and guide clinical practice. To evaluate the adherence of drugs prescriptions in clinical practice according to predefined standards of care, a series of indicators measurable in relation to specific conditions have been developed. This work presents four indicators: the first related to the use of drugs acting on the renin-angiotensin system in patients at high cardiovascular risk; the second related to the use of angiotensin II antagonists with expired patent; the third related the occasional prescription of antihypertensive drugs; and the fourth on the adherence to treatment with antihypertensive drugs. The four indicators were measured in the OsMed database.

Adherence to statin treatment is expected to be associated with health outcomes. Much of the available evidence is derived from studies conducted on selected populations (eg, Medicaid population), on specific cohorts of patients (eg, patients with diabetes mellitus or those who have experienced acute myocardial infarction [AMI]), or with respect to a single outcome (eg, only death or only AMI).The aim of this study was to evaluate the association between adherence to statin therapy and all-cause mortality and cardiovascular morbidity (AMI and stroke) in an unselected cohort of newly treated patients.We performed a population-based retrospective cohort study that included adult patients with a first prescription of a statin from January 1, 2004, through December 31, 2006, using data from the administrative databases of the Local Health Unit of Florence in Italy. Adherence to statin treatment was estimated as the proportion of days covered (PDC) by filled prescriptions and classified as low (PDC, 21%-40%), intermediate-low (PDC, 41%-60%), intermediate-high (PDC, 61%-80%), and high (PDC,80%). Cases with PDC ≤20% were excluded. A Cox regression model was used to investigate the association between adherence to treatment and all-cause mortality and hospitalization for AMI or stroke.The cohort consisted of 19,232 patients (9823 men and 9409 women) aged 18 to 102 years (mean [SD], 66.5 [11.4] years): 20.1% had been previously hospitalized for cardiovascular events and 17.6% had been treated with hypoglycemic drugs. Adherence to statins was low in 4427 patients (23.0%), intermediate-low in 3117 (16.2%), intermediate-high in 3784 (19.7%), and high in 7904 (41.1%). Lower-adherent patients were younger and had fewer comorbidities compared with higher-adherent patients. In our multivariable analyses, high adherence was significantly associated with decreased risk of all-cause death, AMI, or stroke. Compared with low adherence (hazard ratio [HR] = 1), the risk was lower in intermediate-low adherence (HR = 0.83; 95% confidence interval [CI], 0.71-0.98; P0.05) and much lower in intermediate-high (HR = 0.60; 95% CI, 0.51-0.70; P0.001) and high adherence (HR = 0.61; 95% CI, 0.54-0.71; P0.001).In this Italian cohort of newly treated patients, suboptimal adherence to statins occurred in a substantial proportion of patients and was associated with increased risk of adverse health outcomes.

Oral anticoagulant therapy is essential for the treatment and prevention of many thromboembolic disorders. The aim of the present study is to evaluate the level of anticoagulation intensity in patients treated with vitamin K antagonists (VKAs) in a clinical practice setting and to explore the relationship between anticoagulation intensity and adherence to VKA treatment. We conducted a retrospective cohort study using the administrative databases of three Italian Local Health Units. Patients were enrolled if they had filled at least one prescription for VKAs (ATC code B01AA) between January 1st, 2007 and June 30th, 2008. In the same period all determinations of the international normalised ratio (INR) were collected. The parameters evaluated were anticoagulation control and adherence to VKA treatment.The survey showed that only 47.9% and 56.3% of INR determinations, in VKA naïve and established patients respectively, were into the recommended range (2.0-3.0). Moreover, the percentage of INR determination below the recommended range was higher than the percentage of INR determination above the recommended range for both naïve and established patients. Moreover, adherence to VKA treatment was poor both in naïve and established patients and, consequently, anticoagulation control is poor. Also in patients with the highest adherence to VKA treatment, only about 60% of INR determinations were into the recommended range. Our findings evidence that the anticoagulation control in clinical practice settings is still unsatisfactory and it is necessary to evaluate interventions to increase the amount of time at which patients’ INR are within the recommended range.

Objective: To evaluate adherence to antihypertensive therapy (AHT) and the association between adherence to AHT, all-cause mortality, and cardiovascular (CV) morbidity in a large cohort of patients newly treated with antihypertensives in a clinical practice setting. Methods: An administrative database kept by the Local Health Unit of Florence (Italy) listing patient baseline characteristics, drug prescription, and hospital admission information was used to perform a population-based retrospective study including patients newly treated with antihypertensives, ≥18 years of age, with a first prescription between January 1, 2004 and December 31, 2006. Patients using antihypertensives for secondary prevention of CV disease, occasional spot users, and patients with early CV events, were excluded from the study cohort. Adherence to AHT was calculated and classified as poor, moderate, good, and excellent. A Cox regression model was conducted to determine the association among adherence to AHT and risk of all-cause mortality, stroke, or acute myocardial infarction. Results: A total of 31,306 patients, 15,031 men (48.0%), and 16,275 women (52.0%), with a mean age of 60.2 ± 14.5 years was included in the study. Adherence to AHT was poor in 8038 patients (25.7% of included patients), moderate in 4640 (14.8%), good in 5651 (18.1%), and excellent in 12,977 (41.5%). Compared with patients with poor adherence (hazard ratio [HR] = 1), the risk of all-cause death, stroke, or acute myocardial infarction was significantly lower in patients with good (HR = 0.69, P < 0.001) and excellent adherence (HR = 0.53, P < 0.001). Conclusions: These findings indicate that suboptimal adherence to AHT occurs in a substantial proportion of patients and is associated with poor health outcomes already in primary prevention of CV diseases. For health authorities, this preliminary evidence underlines the need for monitoring and improving medication adherence in clinical practice.

Many studies have indicated the adequate use of lipid-lowering drugs (LLDs) as a factor in reducing the risk of cardiovascular disease. However, in clinical practice, a very high percentage of patients are not adequately treated. To analyze the management of hypercholesterolemia in a non-experimental setting and to estimate the factors associated with poor adherence to treatment. A longitudinal study was performed using clinical and demographic data recorded in the General Practitioners’ database. The sample included all patients, aged 30 years or over, with total blood cholesterol measured between 1 January and 31 December 2000. Utilization of LLDs was defined as the standardized daily dose of the drugs purchased during the 12 months preceding the cholesterol measurement. The study included 4764 patients (mean age 59.4±14.1 years, 40.7% males). Of the subjects with a total cholesterol higher than a 6.5 mmol/l, approximately 17% were treated with LLDs. About 39% of the patients with previous atherosclerotic diseases were taking statins. Analysis of patients taking LLDs showed that 40.6% of subjects took less than half of the defined daily dose. Factors associated with poor adherence to treatment were: absence of previous atherosclerotic diseases, absence of concomitant diseases, and smoking. A total cholesterol of less than 5 mmol/l was achieved in 19.9% of patients. Analyzing the data contained in the general medicine database made it possible to evaluate the use of LLDs in clinical practice and to establish the need to pay greater attention to achieving the objective set by the treatment.

Large-scale clinical trials have shown that antihypertensive drugs reduce the risk for cardiovascular events. However, little is known about the effectiveness of these drugs in the primary care setting.The aim of this study was to investigate the frequency of cardiovascularevents during treatment with either of 2 of the most frequently prescribed antihypertensive drugs.This observational, longitudinal, cohort study considered the entirepopulation listed in the administrative databases of the Local Health Authority of Ravenna, Italy (356,000 residents). The demographic registry and the pharmaceutical and nosocomial databases were cross-linked to determine drug treatment, as well as the frequency of cardiovascular events on a patient-by-patient basis. Each patient aged18 years receiving a first prescription for amlodipine or enalapril in the period between January 1, 1996, and December 31, 2000, with ≥6 months of continuous treatment with the drug was included. The follow-up period varied from 6 months to 4.5 years.Of the 7500 patients analyzed (4092 women and 3408 men; mean[SD] age, 68.0 [12.4] years), 2231 (29.7%) were given amlodipine and 5269 (70.3%) were given enalapril. The observed rate of cardiovascular events was higher among patients treated with amlodipine (54 per 1000 patient-years vs 46 per 1000 patient-years; P = 0.007), with a hazard ratio 17% higher compared with enalapril (95% Cl, 5.0-24.0; P = 0.007). The result was also confirmed using Cox multivariate regression analysis. The combination of enalapril plus diuretic showed the lowest risk for cardiovascular events (0.73; 95% Cl, -36.0 to -16.0; P0.001).This analysis showed that treatment with enalapril was associatedwith a significantly lower frequency of cardiovascular events compared with amlodipine.

This review highlights the effects incurred on pharmacoutilization and the total expenses for dyspeptic syndrome by the introduction of a clinical guideline. A retrospective method of reading an administrative billing database in the Ravenna (Italy) local health unit was performed for all subjects who were health-assisted by ten general practitioners. They had previously developed and agreed to a clinical guideline to manage dyspeptic syndrome patients (study group) and a group of 30 self-regulating general practitioners patients (control group). Patients were classified as dyspeptic according to the presence of at least one prescription for antidyspeptic drugs during a 365-day follow-up period. The cost for drugs, hospitalizations, emergency room accesses and gastroscopies was recorded. The results showed that a total of 51,904 subjects were enrolled: 23.1% by the study general practitioners and 76.9% by the control general practitioners. The percentage of dyspeptic patients accounted for 17.6 and 15.0% in the subjects enrolled in the study and control groups. The total average cost of the dyspeptic patients was less in the study than in the control group (euro163.41 vs. 181.39; p = 0.043). This difference is mainly due to the cost of hospitalization (euro94.55 in the study and euro110.92 in the control group; p = 0.012). The significant results of the introduction of a guideline for the treatment of dyspeptic syndrome into clinical practice were an increase in the use of pharmacological treatment and a decrease in the cost of treatment per patient.

The objective of the research was to perform a clinical practice-based analysis of how long patients remain on various antihypertensive drugs. An administrative database listing of patient baseline characteristics, drug prescriptions, and hospital admissions was used. All new users of antihypertensive drugs,or =20 years of age, receiving a first prescription for diuretics, beta blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor antagonists between January 1, 2000, and December 31, 2000, were included and observed for 365 days. Persistence was defined as a duration of therapy273 days. A total of 14,062 patients were included in the study, 39.7% of whom remained on treatment (persistent patients). Persistent patients were more likely to be older, taking other drugs for concurrent disorders, hospitalized for cardiovascular diseases, and initially prescribed angiotensin II receptor antagonists. Persistent patients accounted for 80.6% of the overall cost for antihypertensive drugs. Factors associated with drug cost were age, pattern of persistence, number of prescribed classes, and specific medication at enrollment. Measuring persistence with treatment is needed to evaluate the appropriateness and the cost-effectiveness of drug use.

An observational study was performed to compare five compounds as initial therapy to evaluate the persistence with antihypertensive treatment and drug cost. Over a 1-year follow-up period on the entire population (approximately 360,000 residents) of the Ravenna Local Health Unit. The presence of five major antihypertensive agents between January 1st, and December 31st, 1997 was investigated. There were 4614 patients enrolled. The annual average cost of treatment ranged between euro 44.27 (95% confidence interval, 38.18-52.06) for patients started on atenolol to euro175.65 (150.37-205.10) for those started on losartan. Patients who began losartan showed a higher posterior probability of an effective antihypertensive treatment. On average, these patients turned to produce cost-effective treatment with an average probability of 0.70.

In spite of findings of large-scale clinical trials which showed an overall reduction of morbidity and mortality from coronary heart disease in patients treated with 3-hydroxy-3-metylglutaryl coenzyme-A reductase inhibitors (statins), relatively little is still known about the real prevalence of treatment in general practice setting, particularly in patients with a high cardiovascular risk. The objective of this study was to investigate among patients with cardiovascular risk profile estimated according to the Framingham Heart Prediction Risk Study, the percentage of those exposed to statins, and the proportion of patients reaching total cholesterol (TC) target levels. A cross-sectional analysis was conducted on a large cohort of patients listed in the administrative databases of the Local Health Unit of Ravenna (total resident population of 356,000). In 2001, every single patient who received a prescription for a statin, and/or with a recorded plasma TC level, and/or with a hospital admission for cardiovascular reasons (identified by ICD-9 code), and/or with a clinical appraisal based on the presence of cardiovascular risk factors, was defined eligible. Sebsequently, pharmaceutical, and nosocomial databases, were cross-linked with that of 50 general practitioners in order to assess the pharmacoutilization of statins on a patient-by-patient basis. A cohort of 9,208 patients with a well documented cardiovascular risk profile were analyzed. The mean age of those patients was 57 (SD=17) years and 42% of them was male. On the basis of raised TC levels and cardiovascular risk profiles, patients for whom a statin treatment was suggested amounted to 7,233. However, the number of those who received statins was significantly lower (n = 1,343), corresponding to 18.6%. In those exposed to statins, just a small group of patients reached a level of TC below 190 mg/dl (n = 271), equivalent to 20.2%. In the group of treated who did not achieve recommended TC target levels, 31.7% (n = 340) of patients was at very high cardiovascular risk. Moreover, among all patients with high plasma TC levels (n=5,890), there was a 45.7% (n = 2,690) who did not received any lipid lowering drug even though they had a high cardiovascular risk profile. Results from large population-based administrative databases suggest a remarkable level of undertreatment among patients with cardiovascular risk factors. Furthermore, many patients did not achieve recommended TC target levels with their statin treatment. Pharmacoutilization of statins in general practice reveals the need of a more careful pursuing of therapeutic goals.

A new class of anti-inflammatory agents, the selective inhibitors of cyclooxygenase-2 (COXIBs), has been recently introduced into the market for the treatment of osteoarthritis and reumatoid arthritis. Randomized and controlled clinical trials showed a similar efficacy and a better tolerability profile of COXIBs compared with conventional non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to perform a scientific literature review relating to the economic impact produced by COXIBs’ introduction. The research of references included the following databases: MEDLINE, EMBASE and the NHS (Economic Evaluation Database) of the York University. A total of 67 in extenso pubblications have been extracted. Of these 13 papers having the specific objective to evaluate the economic implications of COXIBs in comparison to conventional NSAIDs was analysed. In ten cases (77%), cost-effectiveness analyses were performed. The European context was considered in eight cases (62%), while that of North America and Asia were investigated in four and one case, respectively. The analysis of costs took always into account direct costs of the management of arthritis exclusively (drugs, and resources associated with the treatment of gastrointestinal side effects). Indirect and intangible costs were never considered. The results of this review highlight that the higher tollerability profile of COXIBs may generate a cost-saving. This cost-saving seems to be basically due to the reduced frequency of gastroprotective agents coprescription and also to a lesser appearance of severe gastrointestinal side effects compared with conventional NSAIDs. Besides the disease management improving, the cost-saving associated with COXIBs can completely or partially offset the net increase of expense induced by their higher price of purchase.

The aim of the paper was to perform a pharmacoepidemiological and pharmacoeconomic analysis of antihypertensive drug treatment. An administrative database kept by the Local Health Unit of Ravenna listing patient baseline characteristics, drug prescriptions and hospital admissions was used to perform a population-based cohort study. The study included all new users of antihypertensive drugs, 20 years of age or over receiving a first prescription for diuretics, beta-blockers, calcium channel-blockers, ACE inhibitors or angiotensin II antagonists (AIIAs) between January 1st, 2000 and December 31st, 2000. All prescriptions for anti-hypertensive drugs filled during the 12-months follow-up period were considered. Patients were classified as continuers, switchers and discontinuers on the basis of their prescription dynamics. A total of 14.062 patients were included in the study of whom only 39,7% resulted persistent at 12 months. Patients initially prescribed for AIIAs were more likely to continue antihypertensive treatment than those started on other drug classes as well as those with older age, concurrent drug therapies and previous hospitalisation for cardiovascular diseases. The overall cost of the study cohort for antihypertensive drugs amounted to 1.238.752,37 euros of which 80,6% was used for persistent patients. The annual average cost for antihypertensive drugs was 171,73 euro for continuers, 205,10 euros for switchers and 28,29 euros for discontinuers. Factors associated to drug cost were age, pattern of persistence, number of prescribed drug classes, and class prescribed at enrolment. Nonpersistence with antihypertensive pharmacotherapy induced a high cost for the consumption of antihypertensive drug since discontinuers are responsible for a significant percentage of drug resources allocated on subjects exposed to therapy. A correlation between drug therapy cost and persistence with treatment is needed to evaluate the appropriateness of drug utilization and to perform cost-effectiveness analyses between alternative pharmacological agents.

In this study, the persistence with treatment and resources allocated in antihypertensive pharmacotherapy has been evaluated. Administrative databases of the Local Health Unit of Ravenna listing patients baseline characteristics, drug prescriptions and hospital admissions were used to perform a population-based retrospective study. All new users 20 years old or over receiving a first prescription for diuretics, beta-blockers, calcium channel-blockers, ACE inhibitors or AII-Antagonists between January 1st, 1997 and December 31st, 1997 were included. A one-year follow-up for prescriptions of anti-hypertensive drugs were considered. According to duration of therapy, treated population was divided in persistent patients (continuers and switchers) and non-persistent patients. A total of 16,783 patients was included in the study of whom 64.9% were non-persistents. Persistence with treatment seems to be associated with the class of anti-hypertensive drug initially prescribed, and with patient-related factors. Patients initially prescribed for AII-Antagonists were more likely to persist than those starting on the other antihypertensive classes. Annual antihypertensive treatment cost accounted for • 1,076,053.55 of which 25.4% for non-persistent patients. An appropriate use of claims data may be considered as a powerful tool, providing detailed epidemiological and economic information concerning the antihypertensive treatment.

Many hypertensive patients discontinue drug therapy despite the increased cardiovascular risk associated with inadequately controlled hypertension. However, most experiments do not address this premature discontinuation of therapy, making it difficult to project the appropriateness of antihypertensive drugs in real-world use.The goal of this study was to assess patients' persistence with antihypertensive drug therapy in a nonexperimental setting.An administrative database kept by the Local Health Unit of Ravenna, Ravenna, Italy, listing patient baseline characteristics, drug prescriptions, and hospital admissions was used to perform a population-based, retrospective study. The study included all patients who met the following criteria from January I through December 31, 1997: new user of antihypertensive drugs;or = 20 years of age; receiving a first prescription for a diuretic, beta-blocker, calcium channel blocker, angiotensin II-receptor antagonist (AIIA), or angiotensin-converting enzyme inhibitor. All prescriptions for antihypertensive drugs filled during the 12-month follow-up period were used to define patients as continuers, switchers, or discontinuers on the basis of their persistence with therapy.A total of 16,783 patients were included in the study analyses: 7,409 men (44.1%) and 9,374 women (55.9%), with an average age of 56.1 +/- 18.3 years (range, 20-105 years). Of this study population, 64.9% (n = 10,894) discontinued treatment over the course of follow-up, 26.9% (n = 4508) continued treatment with the initially prescribed medication (with 5.1% [n = 862] adding another medication for combination therapy), and 8.2% (n = 1381) switched medications. Patients initially prescribed AIIAs were more likely to continue treatment than those initiated on other types of antihypertensives (P0.001). Discontinuation was associated with younger age, lower prevalence of concurrent chronic pharmacotherapies, and lower prevalence of previous hospitalizations for cardiovascular disease (all P0.001).Health care claims data are a powerful tool for measuring continuation of therapy, providing detailed, populationwide epidemiologic and economic information for analyzing antihypertensive drug treatment. Further studies are required to relate pharmacotherapy to outcomes.

In the clinical-practice setting, only a small percentage of patients treated with antihypertensive drugs become normotensive. Furthermore, the diversity of drug classes used makes comparison of treatments difficult.The goal of this study was to characterize the types and efficacy of antihypertensive treatments used in primary care in the area of Ravenna, Italy. The study was conducted in the context of the PANDORA Project, an open-ended global outcome study.Data were gathered from general practitioners (GPs) and were stored by the GPs or through links with national health service databases. The population of interest was patients with essential hypertension taking antihypertensive medication, each of whom was observed for 365 days. Blood pressure was measured in the morning or afternoon using an automated device, in accordance with normal clinical practice. At each office visit, the GP reviewed and made any necessary adjustments to the patient's antihypertensive treatment. Antihypertensive drug use was assessed by calculating the mean daily dose (MDD) of the prescribed drug and the duration of treatment (DT). A DTor = 273 days constituted continuous therapy, and a DT273 days constituted discontinuous therapy. Adverse events were not collected.Twenty-one GPs took part in the study. The study population included 969 patients (443 men, 526 women), all of them white, whose ages ranged from 23 to 88 years. At enrollment, 327 patients were normotensive (blood pressure140/90 mm Hg) and 642 were hypertensive despite drug treatment. More than 25 treatment regimens were identified. Over the course of follow-up, 49 patients had discontinuous therapy and 920 had continuous therapy. Among those who had continuous therapy, 117 (12.7%) took an MDD of0.5 tablet/d; 297 (32.3%) tookor = 0.5 and1 tablet/d; 364 (39.6%) tookor = 1 and2 tablets/d; and 142 (15.4%) tookor = 2 tablets/d. At the end of the observation period, the proportion of normotensive patients had increased by 5.7% (P0.001).Based on the findings of this study, improper use of antihypertensive drug therapy appears to be one of the reasons for the relatively small proportion of patients who attain blood pressure control with treatment.

The Pandora Project is a longitudinal database--implemented by general practitioners since June 1997 in the Ravenna area (Italy)--providing information on patients with hypertension. Data from 1,651 patients were followed up for I year in order to investigate the cost of hypertension. Only direct medical costs were considered in the perspective of the National Healthcare System.At enrollment, 552 patients were classified as normotensive, 1,099 as hypertensive. After 1 year, among normotensive group, 352 patients remained normotensive and 200 became hypertensive; among hypertensive group, 323 patients became normotensive and 776 remained hypertensive. The average total cost per patient at follow-up was 779.59 Euros. About 46% of total cost was due to anti-hypertensive therapy, irrespective of the evolution of blood pressure levels registered, whilst other direct costs represented 54% of total patient cost in all cohorts. It is possible that co-morbidities play a significant role in this situation. Patient aged 80-89 years generate higher costs. Even if further investigation is needed on the burden of comorbidity on a per-patient cost of hypertension, this work provides evidence that the average total cost per patient is likely to increase with age and co-morbidities. Key words: cost-of-illness, costs, economics, hypertension.

Nowadays a large amount of medical data are available, although they are not always homogeneous, they arise from different backgrounds and are used for different purposes. The aggregation of these data could give huge boost to the epidemiology and, in particular, to nephrology. In many parts of Italy there is the aim to reorganize the hospital health care, as well as the territorial setting. In this framework, the role of nephrology is evaluated without data to support the ongoing decisions, therefore the linkage among the data stored in the administrative and clinical databases of the Local Health Unit could contribute to the planning of nephrological (but not only) activities, in order to ensure the best cost-effectiveness possible for each different reality.

Luca Degli Esposti, Stefania Saragoni, Stefano Buda, Ezio Degli EspostiClicon Srl Health, Economics and Outcomes Research, Ravenna, ItalyObjective: To investigate the criteria for prescribing a combination pill for hypertensive patients, and whether the combination pill improves medication adherence.Materials and methods: This was a retrospective cohort study, performed in three Italian local health units. We selected all adult subjects who received at least one prescription of antihypertensive drugs between September 1, 2011 and December 31, 2011 (the enrollment period). The date of the first antihypertensive claim was defined as the index date. For each patient, we documented the antihypertensive drug treatments and evaluated patients’ adherence to treatment, which was calculated, separately, as the proportion of days covered in the two 6-month periods preceding and following the index date. Only patients treated with olmesartan and/or amlodipine as a single therapy, or as a two-pill combination in the period prior the index date were included. Changes in adherence levels were compared in subjects who moved to the fixed combination of olmesartan/amlodipine after the index date and in subjects who did not.Results: A cohort of 21,008 subjects with a 6-month history of a prescription of olmesartan and amlodipine as two pills in a combination treatment, or as single-pill treatment, was obtained. Subjects treated with the two-pill combination treatment moved to the olmesartan/amlodipine fixed combination treatment more frequently than did subjects with a single-pill treatment (P

INTRODUCTION Venous thromboembolism (VTE) is a well-known complication of total hip replacement (THR) and total knee replacement (TKR). Various drugs have been introduced in an attempt to reduce the mortality as well as the short-term and long-term morbidity associated with the development of VTE. The aim of this study was to analyze drug utilization for thromboprophylaxis and the cost of illness in real clinical practice in patients with THR or TKR. MATERIALS AND METHODS A multicenter, retrospective, observational cohort study based on local health unit administrative databases was conducted. All patients (≥18 years old) discharged for THR/TKR procedures between January 1, 2007 and December 31, 2008 were included in the study. The date of first hospital discharge was the index date; patients were followed up for a period of 12 months. RESULTS A total of 10,389 patients were included: 3516 males (33.8%, 69.4 ± 10.4 years) and 6873 females (66.2%, 71.7 ± 9.0 years), of which 5483 (52.8%) were discharged for THR and 4906 (47.2%) for TKR. First antithrombotic treatments after discharge were enoxaparin (3937, 37.9%), heparin (3752, 36.1%), antiplatelet agents (658, 6.3%), vitamin K antagonists (276, 2.7%), fondaparinux (136, 1.3%), combinations (185, 1.8%), and no therapy (1445, 13.9%). Overall, we observed 2347 (22.6%) treatment changes; median duration of antithrombotic treatment was 23 days (range 11-47) for THR and 22 days (range 11-46) for TKR. During the follow-up period, we observed 129 cases of VTE (120 per 10,000 patients), five post-thrombotic syndrome (4.8 per 10,000 patients), and three heparin-induced thrombocytopenia (2.9 per 10,000 patients). Median cost for both THR and TKR was €9052.00 (range €8063.00-€9084.96), with a median length of stay of 9.0 days (range 6.0-12.0).

The primary aim of the STAR Study (Statins Target Assessment in Real practice) was to determine the LDLcholesterol reduction and to analyse patient’s and therapeutic factors associated to LDL-cholesterol target attainment in newly treated subjects with statins in an unselected population in clinical practice setting. Administrative databases (including pharmaceutical prescriptions and hospital admissions) and laboratory test databases (including LDL-cholesterol values) of five Local Health Units, distributed in Emilia Romagna, Toscana and Umbria, were linked. A retrospective cohort study was conducted and all subjects aged ≥18 years with a first prescription for statins (newly treated subjects) between January 1st, 2007 and June 30th, 2008 were included. All statin prescriptions over a 12 months follow-up period were considered and used to calculate adherence to treatment. Baseline and follow-up LDL-cholesterol, respectively, were defined according to the nearest determination to the first prescription for statins and to the end of the follow-up period. A total of 3.232 subjects was included, 1.516 males (47%) and 1.716 females (53%), with an average age equal to 65,9 ± 11,3 years. Among included subjects, 22,6% had a gap to LDL-cholesterol target

The objective of this paper is to evaluate persistence with treatment and resources allocation in antihypertensive pharmacotherapy in a 'real world' population. An administrative database listing all purchased drugs was used to perform a longitudinal analysis. The study included all new users over 20 years of age receiving a first prescription for amlodipine, atenolol, fosinopril, indapamide, or losartan, in an enrolment period of 12 months. The follow-up period lasted 12 months. According to prescriptions dynamics, subjects were classified as same therapy, combination, switching, interruption and occasional utilization. The 34.9% study cohort, persisted with treatment (21.1% on same therapy, 4.7% on combination and 9.1% on switching), while 65.1% did not persist (10.9% on interruption and 54.2% on occasional use). The overall drug cost accounted for persistent (69.0%) and nonpersistent subjects (31.0%). The annual average cost ranged from euro32.80 for occasional users to euro274.69 for those in combination. In clinical practice, a high percentage of patients do not receive adequate antihypertensive therapy, since the 65.1% of subjects did not persist with treatment. This results in a level of pharmaceutical expenditure that cannot be considered appropriately allocated.

This study determined the prevalence of 3 categories of body mass index (BMI)--normal weight, overweight, and obesity--in a sample of subjects from general clinical practice in Ravenna, Italy, and evaluated the impact of comorbidities associated with overweight and obesity on the costs of drug treatment from the perspective of the Italian national health system.This was a cross-sectional study conducted in a sample of subjects agedor =18 years from 10 general practices in the Ravenna local health unit (LHU) in 2001-2002. Subjects were invited to attend a screening visit at which weight and height were measured for determination of BMI, blood pressure was measured, and a fasting blood sample was obtained for laboratory tests. The screening examinations were conducted by 2 physicians at a dedicated practice. Normal weight, overweight, and obesity were defined as a BMIor =24.9, between 25 and 29.9, andor =30 kg/m2, respectively. The costs of classes of drug treatment that were reimbursable to the LHU in the 12 months before the screening examination were evaluated using the Ravenna LHU administrative databases. Drug treatments were classified as antihypertensive agents, statins, NSAIDs, gastroprotective drugs, antidiabetic agents, respiratory drugs, antiplatelet agents, antidepressants, and all other drugs. The data were analyzed by age group.Of the 2622 subjects in the sample, 1256 (47.9%) had a normal BMI, 918 (35.0%) were overweight, and 448 (17.1%) were obese. The prevalence of overweight and obesity increased in relation to age up to 50-59 years (P0.001), after which it remained stable. Overweight and obese subjects had significantly more exposure to individual and multiple drug treatments compared with subjects with normal weight (P0.001). By type of drug treatment, 16.7% of normal-weight subjects, 35.6% of overweight subjects, and 51.8% of obese subjects were exposed to antihypertensives; 4.1%, 8.7%, and 12.1%, respectively, to statins; 14.2%, 22.0%, and 29.0% to NSAIDs; and 1.0%, 4.7%, and 9.4% to antidiabetics. The mean annual cost of drugs was Euro 132.71 in normal-weight subjects, Euro 246.19 in overweight subjects, and Euro 335.64 in obese subjects (P0.001). After adjustment for differences in age distribution between the study sample and the overall population of Ravenna, the estimated excess drug costs associated with overweight and obesity in Ravenna were Euro 5,661,126.20 and Euro 6,688,099.85, respectively.In this study sample, the prevalence of overweight increased by approximately 10% and the prevalence of obesity increased by approximately 5% with each decade of age up to 60 years, after which it remained stable at approximately 40% and approximately 20%, respectively. Overweight and obesity were associated with increased drug exposure and costs in all age groups considered.

Global risk status more than BP values per se drive nowadays treatment decisions and increasing emphasis is given to the role of lipid control in hypertension (HT). However, the distribution of circulating low density lipoproteins (LDL) levels as a function of risk profile and lipid-lowering treatment in hypertensive patients is unclear.We analysed 1196 patients (677 males, age range: 20-80 years) referred to our Hypertension Unit with treatment history and a complete dataset (systolic blood pressure levels, being on anti-hypertensive treatment or not, total and high density lipoproteins (HDL) cholesterol, smoking status, sex, age) for 10-year absolute coronary heart disease (CHD) risk stratification by National Cholesterol Education Program (NCEP)/ATP III guidelines. LDL cholesterol25.9 mmol/L (100 mg/dL) was the target for high-risk patients (vascular diseases, diabetes, hypertension with multiple risk factors at CHD risk20%/10 years). LDL33.6 mmol/L (130 mg/dL) and 41.4 mmol/L (160 mg/dL) were the thresholds for intermediate (10-20%/10 years) and low (10%/10 years) CHD risk.At referral, 78% of high-risk patients were above target LDL and, overall, 56% had LDL cholesterol above the desired risk-specific thresholds. Lipid-lowering treatment was prescribed in 19% in whom LDL was actually higher than the untreated group.LDL cholesterol was out of target in most of a large series of referred high-risk hypertensive patients and LDL levels were largely unsatisfactory even in those undergoing lipid-lowering treatment. The data show the intensive effort still needed to implement global risk-oriented prevention strategies in hypertensive populations.

The aim of our work was to evaluate, in a general practice setting, the attitude of general practitioners in determining the individual coronary risk.The coronary risk was determined among patients aged 30 to 74 years using the following parameters: gender, age, smoking habits, diagnosis of diabetes mellitus, systolic blood pressure, and total cholesterol. We evaluated the records of 446,331 subjects collected by 481 general practitioners working throughout Italy.Except for age, gender and diabetes mellitus, risk factors were largely under-recorded: blood pressure in 37.0% of the total patients, total cholesterol in 34.3%, smoking habits in 21.9%. Recording was substantially low even in patients who were prescribed with antihypertensive drugs and/or lipid-lowering drugs: blood pressure in 80.6% of the patients, total cholesterol in 69.1%, smoking habits in 46.1%. Cardiovascular risk factors were more frequently recorded as age increased and slightly more among women as compared to men. Obviously, it is possible that risk factors had been assessed but not recorded.Cardiovascular risk factors are substantially under-recorded among Italian general practitioners thus impairing adequate preventive treatment. A systematic, well programmed approach may theoretically lead to evaluate the majority of the target population within a few years.

Despite randomized and controlled trials indicating continuous treatment with statin therapy as a factor in reducing morbidity and mortality after acute myocardial infarction, records reveal a high percentage of patients at risk who are either not receiving treatment or being treated inadequately.An administrative database kept by the Local Health Unit of Ravenna and listing patient baseline characteristics, drug prescriptions and hospital admissions was used to perform: 1) an analysis of patients discharged alive from hospital each year between 1996 and 2000 with a diagnosis of acute myocardial infarction, and 2) a retrospective cohort study of drug utilization, and particularly the use of statins, year by year. All prescriptions for statins filled in the 6 months after hospital discharge were considered and used to classify patients in terms of their exposure to statin therapy and of their pharmacoutilization.A total of 2265 subjects were enrolled (446 in 1996, 440 in 1997, 443 in 1998, 443 in 1999, and 493 in 2000). The percentage of patients treated with statins increased each year (from 22.6% in 1996 to 43.8% in 2000) as did the percentage of adequately dosed patients (from 4.3% in 1996 to 23.9% in 2000). The overall cost of dispensed statins amounted to 10,610 euros in 1996 and 45,102 euros in 2000. The proportion of cost for statins accountable to adequately dosed patients ranged from 36.4% in 1996 to 77.4% in 2000. The average cost per adequately dosed patient ranged from 203.40 euros in 1996 to 296.00 euros in 2000 and increased year by year.Pharmacoutilization of statin therapy was found to be unsatisfactory in each study year. Interestingly, however, the trend indicated by the study suggests increasing percentages of patients being exposed to the treatment, and of adequately dosed patients. These results may be attributed to a greater awareness of the need for proper treatment, and may be considered as reflecting a significant improvement in drug management.

Luca Degli Esposti, Stefania Saragoni, Stefano Buda, Ezio Degli Esposti Health, Economics and Outcome Research, Clicon Srl, Ravenna, ItalyObjectives: To compare clinical outcomes and health care costs across three cohorts of uncontrolled diabetic patients who initiated treatment with one of the following: sulphonylureas (SU), thiazolidinediones (TZD) or sitagliptin (SITA).Materials and methods: We performed a retrospective study based on a linkage between administrative and laboratory databases maintained by three Italian local health units. The index period ranged from July 2008–June 2010. Patients were treatment-naïve to either SU, TZD, or SITA, but they were already treated with other oral hypoglycemic agents. Demographics and clinical characteristics were assessed at baseline. Adherence was measured by the medication possession ratio and adherent was defined a patient with a medication possession ratio of 80% or greater. We used a Poisson regression model to estimate the risk ratios for disease-related hospitalizations that occurred during the 18-month follow-up period. The total annual costs included all the pharmacological treatments and the direct costs due to hospitalizations and outpatient services.Results: We identified 928 patients treated with SU, 330 patients treated with TZD, and 83 patients treated with SITA. SITA patients were significantly younger and with fewer previous hospital discharges. The baseline mean glycated hemoglobin level was 8.1% for SU, 8.0% for TZD, and 8.3% for SITA patients. SITA-naïve patients resulted more adherent than the SU- and TZD-naïve patients (79.5% versus 53.2% and 62.8%, respectively; P

The Pandora Project was designed to develop a computer-assisted system to improve the appropriateness and effectiveness of hypertension treatment in clinical practice and to organize a database both for epidemiologic and economic assessments. The feasibility study was conducted by five general practitioners (GP) who enrolled 244 patients over a period of 6 months. The follow-up lasted 6 months. The computer system implemented provided a linkage among GP's office, hypertension unit, Ravenna Health Service databases, and a remote station. A total of 209 patients completed the follow-up period; 56% of patients were not normotensive despite the antihypertensive treatment. The prevalence of overweight, physical inactivity, and family history of high blood pressure and hypercholesterolemia was greater than 50%. Unplanned check-ups by GP occurred 9%. Six patients were admitted to the hospital eight times; 19 patients attended the casualty department 21 times. The mean total direct cost per patient was 567,800 Italian Lire (ITL) and increased to ITL 732,000 or to ITL 825,900 when lost productivity, calculated according to two different formulas, was added. This pilot study confirms the need and feasibility of implementing the Pandora Project in general practice in Ravenna.

In this paper we report some results of our studies on patients with immunoglobulin (Ig)A nephropathy regarding (1) the familiar aggregation of erythrocyte sodium-lithium (Na,Li) countertransport; (2) the association of Na,Li countertransport with the presence of arterial hypertension and lipid abnormalities; (3) the correlation between Na,Li countertransport activity and renal functional reserve; and (4) the preliminary results of a longitudinal study. In 13 families of patients with IgA nephropathy, selected because both parents were available, we found a significant correlation between midparent and offspring Na,Li countertransport activity (Spearman's rank correlation = 0.65; P = 0.023), but no husband-wife relationship. In 49 patients, the activity of Na,Li countertransport was significantly higher in erythrocytes from 20 hypertensive patients than from either 29 normotensive patients or from 36 healthy age- and sex-matched normal subjects. Hyperlipidemic patients had an erythrocyte Na,Li countertransport activity significantly higher than normolipidemic patients and controls. In 17 patients a significant inverse correlation was found between the peak variation of creatinine clearance over baseline value after an oral protein load and the erythrocyte Na,Li countertransport activity (Spearman r = 0.54; P = 0.03). In a longitudinal study of 36 patients followed from 12 to 36 months, those showing a progression toward renal failure had an erythrocyte Na,Li countertransport activity higher than median value. The results of our studies show that in patients with IgA nephropathy a high erythrocyte Na,Li countertransport rate, genetically determined, is associated with the presence of arterial hypertension and lipid abnormalities, and perhaps with a less favorable disease outcome.

Objective: To perform a time-trend analysis of adherence and cost of antihypertensive treatment over four years. Methods: A population-based retrospective cohort study was conducted. We included subjects ≥18 years, and newly treated for hypertension with diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers between 01 January 2004 and 31 December 2007. One-year adherence to antihypertensive therapy was calculated and classified as low, low-intermediate, intermediate, high-intermediate, and high. The direct cost of antihypertensive medications was evaluated. Results: We included data for a total of 105,512 patients. The number of newly treated subjects decreased from 27,334 in 2004 to 23,812 in 2007, as well as antihypertensive drug therapy cost which decreased from €2,654,166 in 2004 to €2,343,221 in 2007. On the other hand, in the same time frame, the percentage of adherent newly treated subjects increased from 22.9% to 28.0%. Compared with subjects initiated on angiotensin receptor blockers (odds ratio [OR] = 1), the risk of nonadherence was higher in those initiated on angiotensin-converting enzyme inhibitors (OR = 1.19), combination therapy (OR = 1.44), beta-blockers (OR = 1.56), calcium channel blockers (OR = 1.67), and diuretics (OR = 4.28). Conclusions: The findings of the present study indicate that suboptimal adherence to antihypertensive medication occurs in a substantial proportion of treated patients, and improvements in treatment adherence were obtained but are still unsatisfactory.

Increased sodium-lithium countertransport activity in red cells of IgA nephropathy patients. The aim of this work was to analyze Na,Li countertransport activity in the erythrocytes from patients with IgA nephropathy, in relationship with their blood pressure status and lipid profile Forty-nine patients (32 males, 17 females) with biopsy-proven IgA nephropathy and without significant impairment of renal function (serum creatinine ≤ 1.4 mg/dl) and 36 normal subjects (21 males, 15 females) were evaluated Twenty-nine patients with IgA nephropathy were normotensive and 20 hypertensive (diastolic pressure ≥ 95 mm Hg or treated by antihypertensive drugs). Na,Li countertransport was significantly higher in red cells from hypertensive than from normotensive patients (P = 0.002) and normal subjects (P = 0.0001), (values respectively 309 ± 17; 241 ± 12 and 211 ± 11 µmol/liter RBC/hr); normotensive patients with IgA nephropathy did not differ from controls regarding the Na,Li countertransport rate. A multiple stepwise logistic regression analysis with blood pressure status as the dependent variable and Na,Li countertransport activity, age, serum creatinine, proteinuria, cholesterol, triglycerides, plasma potassium and time from onset as independent variables, indicated an independent significant association for Na,Li countertransport (P = 0.002) proteinuria (P = 0.006), plasma potassium (P = 0.006) and age (P = 0.029). Other tested variables were not independently related to blood pressure status. Hyperlipidemic patients (plasma total cholesterol concentration >200 mg/dl and/or plasma triglycerides >172 mg/dl) had an erythrocyte Na,Li countertransport activity significantly higher than normolipidemic (P = 0.005) and controls (P = 0.001) (values respectively 295 ± 14; 226 ± 12 and 211 ± 11 µmol/liter RBC/hr). A high erythrocyte Na,Li counter-transport rate may be a marker of an increased risk of developing arterial hypertension, lipid abnormalities, and perhaps a more severe renal disease in IgA nephropathy.

We have assessed the peripheral distribution of T cells, using the monoclonal antibodies OKT3, OKT4, OKT8 and LEU7 and the proliferative response to phytohaemagglutinin (PHA), in 10 renal transplant recipients. In each patient, the immunological pattern was evaluated twice, both before and after 1 month of calcium antagonist (calcium channel blockers, CaA) treatment. During treatment with CaA, we have observed both a significant decrease in the mitogenic response to PHA and a significant increase in OKT8 cells. Our data support the hypothesis that CaAs per se may have an immunomodulatory effect on T cell distribution independently of changes in ciclosporin (CS) blood levels. These results could also provide a cellular basis for synergism between CS and CaA.