Pierluigi Russo

The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: A monthly MRI study after triple-dose gadolinium-dtpa

Abstract.Objective:To examine the relationship between inflammation and brain atrophy in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).Methods:Monthly triple-dose gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18. Patients who developed a clinically definite MS (i. e., a second clinical episode) ended the study at the time of the relapse. For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T2 lesion that did not enhance), and the number and volume of T2 hyperintense lesions (T2-LL) and T1-black holes (T1- LL) were calculated. The percentage of brain volume changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy).Results:Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p < 0.001), but not in T2-LL (8.5%, p = ns). PBVC decreased by 1.1% (p < 0.001) in a time-dependent pattern (Kendall coefficient of concordance = 0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman’s R = –0.61; p < 0.001), but not among inactive patients (Spearman’s R = –0.10; p = 0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ß = –0. 83, standard error (SE) = 0.07, p < 0.001].Conclusions:This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.

Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

AIMS Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. METHODS AND RESULTS We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62-0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). CONCLUSION In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas.

Risk factors for uncontrolled hypertension in Italy

To identify factors related to poor control of blood pressure in primary care, we designed a retrospective case–control analysis of clinical and demographic data recorded in the General Practitioners (GP) database. Study data were provided on a voluntary basis by 21 GPs from a practice-based network in primary care. The study included 2519 hypertensive patients enrolled between January 1 and December 31, 2000. The interventions were antihypertensive medication, and the main outcome measures were control of systolic and diastolic blood pressure (BP). The independent variables considered were: age of patient and GP; patient gender, body mass index, history of smoking, diabetes mellitus, or cholesterol tests; family history of hypertension; previous visits for cardiologic, nephrologic, or vascular surgery evaluation; prior hospitalizations for myocardial infarction or heart failure, and number of admissions for surgery; length of patient follow-up, type of antihypertensive medication, mean daily dosage, adherence to the drug regimen, and number of other medications currently being taken by the patient. Blood pressure was uncontrolled (>140/90 mmHg) in 1525 (60%) of the 2519 hypertensive patients enrolled. The presence of diabetes mellitus, increasing patient age, and increasing GP age significantly increased the risk of uncontrolled BP. Factors significantly associated with a reduced risk of uncontrolled BP were the number of other medications currently being taken by the patient and a prior history of MI. We conclude that the failure of antihypertensive medication to adequately control BP is determined by both the patients characteristics and factors related to the patient–doctor relationship. Successful treatment of hypertension requires patient adherence to the regimen that has been agreed on by the patient and the physician.

Cocaine toxic effect on endothelium-dependent vasorelaxation : An in vitro study on rabbit aorta

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

Cost-Analysis of Relapsing-Remitting Multiple Sclerosis in Italy after the Introduction of New Disease-Modifying Agents

Background and objectiveDuring the last decade, several agents have proven to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS), for example interferon-β (IFNβ) and glatiramer acetate. This study aimed to perform a cost-analysis of the treatment of patients with RRMS in Italy after the introduction of these new agents.Study designThis was a retrospective observational study with systematic patient inclusion.Methods and resultsData gathered from 630 patients with confirmed RRMS over a 2-year period were evaluated. Overall, the direct cost over 2 years reached €11 073 100 thousand, corresponding to a per-patient cost of €17 576 (year of costing, 2001). The cost of disease-modifying agents represented approximately 77% of the total expenditure. IFNβ accounted for 94% of the expense of disease-modifying agents, corresponding to a 2-year cost per patient of €20 223. Although glatiramer acetate and immunoglobulins were also associated with a high level of expense, these were prescribed in only 3.8% and 1.1% of patients, respectively. Using regression analyses, IFNβ therapy, disability, number of days spent in hospital per year and the frequency of magnetic resonance imaging procedures were the main predictors of total costs.ConclusionBased on the results of this study, IFNβ treatment considerably modified the management of RRMS and was associated with a rise in cost of treatment per patient.

Dermatan Sulfate versus Unfractionated Heparin for the Prevention of Venous Thromboembolism in Patients Undergoing Surgery for Cancer: A Cost-Effectiveness Analysis

AbstractBackground: In a recent clinical trial, dermatan sulfate was found to be more effective than unfractionated heparin (UFH), but equally well tolerated, for the prevention of deep vein thrombosis (DVT) after major surgery for cancer. Objective: To perform a cost-effectiveness analysis of dermatan sulfate versus UFH in this clinical setting. Design and setting: This was a retrospective economic analysis using data from a randomised clinical trial, and was performed from the hospital perspective. Methods: Clinical event rates were extrapolated from the observed venographic DVT rates, using appropriate assumptions from the scientific literature. The economic effects of switching DVT prophylaxis from UFH to dermatan sulfate and the potential lives saved were assessed by a predictive decision model. Results: The per patient cost, including the burden of residual thromboembolic events and major bleeding complications, was estimated to be 154 euros (EUR) for dermatan sulfate and EUR185 for UFH (1998 values). With reference to a potential target population of 60 000 patients/year undergoing surgery for cancer in Italy, the total prophylaxis-associated cost was EUR9 258 000 for dermatan sulfate and EUR11 096 000 for UFH, whereas the potential deaths from prophylaxis failure were 204 and 392, respectively. This represented a saving of EUR1 838 000 and 188 potential lives per year with the dermatan sulfate option. The final costs and effects were mainly sensitive to variations in the rates of DVT and pulmonary embolism, and to the possible need for 1 extra day of hospitalisation because of the earlier preoperative initiation of dermatan sulfate prophylaxis. Conclusion: dermatan sulfate is more cost effective than UFH for the prevention of postoperative venous thromboembolism in patients with cancer. If the hospital stay needs to be prolonged, then the dermatan sulfate option may involve a small additional cost (EUR47) per potential life saved.

Prescription drug use among older adults in Italy: a country-wide perspective

In Italy, prescription drug costs represent approximately 17% of total public health expenditures. Older adults commonly use multiple drugs and, for this reason, this population is responsible for a large portion of drug-related costs. In 2012, public expenditure for pharmaceuticals in primary care exceeded 11 billion Euros (approximately 15.2 billion US

A comparative economic analysis of simvastatin versus atorvastatin: Results of the surrogate marker cost-efficacy (SMaC) study

), and older adults aged 65 or older accounted for more than 60% of these costs. Recently, increased attention has been focused on studies aimed at monitoring drug use and evaluating the appropriateness of drug prescribing in older adults. In this article, we examined studies that assessed these issues in different settings at a national level. Specifically, results of surveys of prescription drug use in primary care (OsMED), hospital (GIFA, CRIME, and REPOSI) and long-term care (ULISSE and SHELTER) settings are reviewed. Overall, these studies showed that the quality of drug prescribing in older patients is far from optimal. This leads to an increased risk of negative health outcomes and increased health care costs. Data from these studies are valuable, not only to monitor drug use, but also to target interventions aimed at improving the quality of prescribing. Translating the findings of clinical research and monitoring programs will be challenging, but it will lead to quantifiable improvements in the quality of drug prescribing at a national level.

Intraclass differences in the risk of hospitalization for heart failure among patients with type 2 diabetes initiating a dipeptidyl peptidase‐4 inhibitor or a sulphonylurea: Results from the OsMed Health‐DB registry

Health care payers have become increasingly interested in economic analyses to guide the allocation of limited health care resources. The Surrogate Marker Cost-Efficacy (SMaC) study was undertaken to assess the economics of treatment with simvastatin versus treatment with atorvastatin in reducing low-density lipoprotein cholesterol (LDL-C) in patients in 10 European countries, based on the results of a 1-year, double-blind, parallel-group clinical trial. Participants were between 18 and 80 years of age (n = 177; median age, 57; 94 men and 83 women). Entry criteria were a baseline LDL-C value between 4.2 and 7.8 mmol/L (160 to 300 mg/dL) and a triglyceride value < or =4.5 mmol/L (400 mg/dL). Patients were randomly assigned to receive simvastatin 10 mg or atorvastatin 10 mg. At 16 weeks, any patients not reaching their appropriate LDL-C level received simvastatin 20 mg/d or atorvastatin 20 mg/d. Patients were then followed up for a total of 52 weeks. The overall euro cost analysis was based on the weighted average price of each product across all the independent pharmaceutical markets based on official euro conversion rates. Individual country analyses also were conducted in each local currency. Over the 52-week study, there were no significant differences in the percentage of patients achieving an appropriate LDL-C level (simvastatin 48%, atorvastatin 50%). In the overall euro cost analysis, the cumulative cost of atorvastatin (134 euros) was 33% more than for simvastatin (101 euros) during the first 16 weeks. After titration to 20 mg, the total cost of treatment during the 52-week study remained significantly lower in the simvastatin group than in the atorvastatin group (429 vs 538 euros; P<0.0001). In individual country analyses, therapy with simvastatin was significantly less expensive than therapy with atorvastatin in 8 of 10 countries (P = 0.001 to 0.003). In the remaining 2 countries, there was no significant difference in cost. Across the countries included in the evaluation, there was a significant reduction in the cost of getting patients to appropriate LDL-C levels with simvastatin compared with atorvastatin. These results should provide useful information for physicians and payers; however, additional long-term clinical trials are required to assess fully how treatment with atorvastatin affects patient outcomes, safety, and costs.

Cost-effectiveness study of imipenem/cilastatin versus meropenem in intra-abdominal infections.

To re‐analyse data from a previous retrospective study on 127 555 patients, in which we showed that dipeptidyl peptidase‐4 (DPP‐4) inhibitor therapy was associated with a lower risk of hospitalization for HF (HHF) than sulphonylurea (SU) therapy, in order to evaluate intraclass differences among DPP‐4 inhibitors and SUs.