Manuela Casula

Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, double blind, placebo controlled trials

BACKGROUND Although omega-3 fatty acids have well documented properties which would reduce the cardiovascular (CV) disease risk, the evidence from randomized controlled trials (RCTs) remains inconclusive. We performed a meta-analysis of the available RCTs for investigating the CV preventive effect of administrating at least 1 gram/day, and for at least 1 year, omega-3 fatty acid supplements to patients with existing CV disease. METHODS RCTs published up to March 2013 were searched from PubMed, EMBASE, and the Cochrane Library. Two of us independently reviewed and selected eligible trials. RESULTS Of 360 articles retrieved, 11 randomized, double-blind, placebo controlled trials fulfilling inclusion criteria, overall involving 15,348 patients with a history of CV disease, were considered in the final analyses. No statistically significant association was observed for all-cause mortality (RR, 0.89; 95% CI, 0.78 to 1.02) and stroke (RR, 1.31; 95% CI, 0.90 to 1.90). Conversely, statistically significant protective effects were observed for cardiac death (RR, 0.68; 95% CI, 0.56 to 0.83), sudden death (RR, 0.67; 95% CI, 0.52 to 0.87), and myocardial infarction (RR, 0.75; 95% CI, 0.63 to 0.88). CONCLUSION Overall, our results supply evidence that long-term effect of high dose omega-3 fatty acid supplementation may be beneficial for the onset of cardiac death, sudden death and myocardial infarction among patients with a history of cardiovascular disease.

Statins and the Risk of Diabetes: Evidence From a Large Population-Based Cohort Study

OBJECTIVE To investigate the relationship between adherence with statin therapy and the risk of developing diabetes. RESEARCH DESIGN AND METHODS The cohort comprised 115,709 residents of the Italian Lombardy region who were newly treated with statins during 2003 and 2004. Patients were followed from the index prescription until 2010. During this period, patients who began therapy with an antidiabetic agent or were hospitalized for a main diagnosis of type 2 diabetes were identified (outcome). Adherence was measured by the proportion of days covered (PDC) with statins (exposure). A proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS During follow-up, 11,154 cohort members experienced the outcome. Compared with patients with very-low adherence (PDC <25%), those with low (26–50%), intermediate (51–75%), and high (≥75%) adherence to statin therapy had HRs (95% CIs) of 1.12 (1.06–1.18), 1.22 (1.14–1.27), and 1.32 (1.26–1.39), respectively. CONCLUSIONS In a real-world setting, the risk of new-onset diabetes rises as adherence with statin therapy increases. Benefits of statins in reducing cardiovascular events clearly overwhelm the diabetes risk.

Adherence to lipid-lowering treatment: the patient perspective

Despite the widespread prescription of highly effective lipid-lowering medications, such as the HMG-CoA reductase inhibitors (statins), a large portion of the population has lipid levels higher than the recommended goals. Treatment failures have been attributed to a variety of causes but the most important is likely to be poor adherence to therapy in the form of irregular or interrupted intake and the high frequency of discontinuation or lack of persistence. Adherence is a multidimensional phenomenon determined by the interplay of patient factors, physician factors, and health care system factors. Patients’ knowledge and beliefs about their illness, motivation to manage it, confidence in their ability to engage in illness-management behaviors, and expectations regarding the outcome of treatment and the consequences of poor adherence interact to influence adherence behavior. Patient-related factors account for the largest incremental explanatory power in predicting adherence. This article provides an overview of this critical issue, focusing on patient role in determining adherence level to lipid-lowering therapy.

Are generic and brand-name statins clinically equivalent? Evidence from a real data-base

BACKGROUND Use of generic drugs can help contain drug spending. However, there is concern among patients and physicians that generic drugs may be clinically inferior to brand-name ones. This study aimed to compare patients treated with generic and brand-name statins in terms of therapeutic interruption and cardiovascular (CV) outcomes. METHODS 13,799 beneficiaries of the health care system of Lombardy, Italy, aged 40 years or older who were newly treated with generic or brand-name simvastatin during 2008, were followed until 2011 for the occurrence of two outcomes: 1) therapeutic discontinuation and 2) hospitalization for CV events. Hazard ratios (HR) associated with use of generic or brand-name at starting therapy (intention-to-treat analysis) and during follow-up (as-treated analysis) were estimated by fitting proportional hazard Cox models. A Monte-Carlo sensitivity analysis was performed to account for unmeasured confounders. RESULTS Patients who started on generic did not experience a different risk of discontinuation (HR: 0.98; 95% CI 0.94 to 1.02) nor of CV outcomes (HR: 0.98; 95% CI 0.79 to 1.22) from those starting on brand-name. Patients who spent >75% of time of follow-up with statin available on generics did not experience a different risk of discontinuation (HR: 0.94; 95% CI 0.87 to 1.01), nor of CV outcomes (HR: 1.06; 95% CI 0.83 to 1.34), compared with those who mainly or only used brand-name statin. CONCLUSIONS Our findings do not support the notion that in the real world clinical practice brand-name statins are superior to generics for keeping therapy and preventing CV outcomes.

Pentraxin 3 (PTX3) plasma levels and carotid intima media thickness progression in the general population.

BACKGROUND AND AIM Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and, like C-reactive protein, is independently associated with the risk of developing vascular events. Aim of this study was to investigate, in two large population-based surveys, the Bruneck Study and the PLIC Study, whether PTX3 plasma levels predict the progression of common carotid artery intima-media thickness (CCA-IMT), a surrogate marker of atherosclerosis, in the general population during 5 or 6 years of follow-up. RESULTS In the Bruneck Study, PTX3 plasma levels did not predict a faster progression of CCA-IMT either in the carotid artery or in the femoral artery. This finding was confirmed in the PLIC Study where subjects within the highest tertile of PTX3 did not show an increased progression of CCA-IMT. PTX3 plasma levels were also not associated with the fastest maximum IMT progression. In summary, in more than 2400 subjects from the general population, PTX3 plasma level is neither an independent predictor of progression of subclinical atherosclerosis in different arterial territories, including carotid and femoral arteries nor of incident cardiovascular events. CONCLUSION These findings support the relevance of investigating the predictive value of PTX3 plasma levels only in specific settings, like overt CVD, heart failure or acute myocardial infarction.

Prevalence of the Prescription of Potentially Interacting Drugs

The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes “two prescriptions in the same day”, and concomitant medication “the prescription of two drugs with overlapping coverage”. A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ≥70 years. On average, subjects involved in pDDIs received ≥10 drugs. The odds of exposure were more frequently higher for age ≥65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.

Blood pressure and antihypertensive therapy according to the global cardiovascular risk level in Italy: the CHECK Study

Background Elevated blood pressure (BP) is one of the most important modifiable risk factors for cardiovascular diseases. In this study we assessed the excess of cardiovascular risk attributable to high BP and antihypertensive treatment in a sample of Italian patients enrolled by the ‘Cholesterol and Health: Education, Control and Knowledge’ (CHECK) study. Methods CHECK is a large, cross-sectional epidemiological study, which randomly enrolled patients aged 40–79 years from 425 Italian General Practices from March 2002 to April 2004. Among 5731 patients enrolled in the study [49.6% men, mean age (standard deviation) 57.7 (10.3) years], 723 (12.6%) had ‘optimal’ BP, 1496 (26.1%) had ‘high normal’ BP, and 1942 (33.9%) were hypertensive. Results According to the European Guidelines stratification of the cardiovascular risk-excess attributable to high BP, 34.7% of the sample had a low added risk and 53.2% had a moderate-to-very high added risk. The pharmacological therapy was prescribed in 22.3, 43.9, 61.4, and 76.9% of the patients with low, moderate, high, and very high added risk, respectively. Conclusion Overall dietary and drug therapies are under prescribed, as most of the treated patients would require two additional antihypertensive drugs to meet the recommended BP target. This effort could provide significant individual benefit to moderate/high-risk patients.

High-potency statins increase the risk of acute kidney injury: Evidence from a large population-based study

OBJECTIVE To assess the association between acute kidney injury and exposure to either high-potency statins or low-potency statins. DESIGN A population-based, nested case-control study was performed on a cohort of 316,449 patients from Lombardy (Italy) newly treated with statins between 2007 and 2010 aged 40 years or older. 458 patients experienced acute kidney injury within six months after initial statin prescription. Up to four controls were randomly selected for each case. Logistic regression was used to model the outcome risk associated with high-potency contrasted with low-potency statins dispensed at starting therapy, and during follow-up. RESULTS Patients at whom high-potency statins were initially dispensed were more likely to be hospitalized for acute kidney injury within six months after starting treatment than those on low-potency statins (adjusted OR 1.54, 95% confidence interval 1.25-1.91). Patients receiving high-potency statins within three weeks before the outcome onset had a significant increased risk respect to those who did not receive statins during the same time-window (adjusted OR 1.45, 95% confidence interval 1.04-2.03). When follow-up was extended from 6 months to 12 months the difference was not significant anymore (adjusted OR 1.17, 95% confidence interval 0.89-1.54). CONCLUSIONS Use of high-potency statins is associated with an increased risk of acute kidney injury compared with low-potency statins in the first 6 months after starting therapy.

Incretin-based drugs and risk of acute pancreatitis: A nested-case control study within a healthcare database

To assess the association between use of incretin-based drugs for diabetes mellitus and the occurrence of acute pancreatitis. A population-based, nested case-control study was performed within a cohort of 166,591 patients from the Lombardy region (Italy) aged 40 years or older who were newly treated with oral antihyperglycaemic agents between 2004 and 2007. Cases were 666 patients who experienced acute pancreatitis from April 1, 2008 until December 31, 2012. For each case patient, up to 20 controls were randomly selected from the cohort and matched on gender, age at cohort entry, and date of index prescription. Conditional logistic regression was used to model the risk of acute pancreatitis associated with use of incretin-based drugs within 30 days before hospitalization, after adjustment for several risk factors, including the use of other antihyperglycaemic agents. Sensitivity analyses were performed in order to account for possible sources of systematic uncertainty. Use of incretin-based drugs within 30 days was reported by 17 (2.6%) cases of acute pancreatitis versus 193 (1.5%) controls. The corresponding multivariate odds ratio was 1.75 (95% confidence interval, 1.02 to 2.99). Slightly lower and no significant excess risks were observed by shortening (15 days) and increasing (60 and 90 days) the time-window at risk. This study supports a possible increased risk of acute pancreatitis in relation to use of incretin-based drugs reported in a few previous studies. However, given the potential for bias and the inconsistency with other studies, additional investigations are needed to clarify the safety of incretin-based-drugs.

Reaching LDL-c targets in high-risk patients requires high-efficacy cholesterol-lowering drugs in more than 50% of cases. The results of the CHECK study.

We estimated the need to use low-efficacy statins or high-efficacy statins or drug combinations to bring high- or very-high cardiovascular risk subjects to their LDL-c target, in a sample representative of the Italian adult population and according to the principles of reimbursement of hypercholesterolemic drugs currently used in Italy. The results allow us concluding that among high or very high cardiovascular risk patients about three patients out of five should be prescribed high-efficacy statins or drug combinations. The other two prescriptions might take into account lower-efficacy statins. If we also compute the values of HDL-c in these subjects--the large majority of which stands below the optimal values as suggested by International guidelines--we bring forward the need either to select specific statins able to increase the levels of these protective lipoproteins or to consider combination therapies of statins with fibrates or nicotinic acid. Our data might conceivably be applied to other low-cardiovascular risk countries and should be taken into account when defining the proportion of drugs with different efficacy and cost in the everyday clinical practice.