Impact of COVID-19 Pandemic on Adherence to Chronic Therapies: A Systematic Review.

The spread of the coronavirus disease 2019 (COVID-19) pandemic caused a sudden and significant disruption in healthcare services, especially for patients suffering from chronic diseases. We aimed at evaluating the impact of the pandemic on adherence to chronic therapies through a systematic review of available studies. PubMed, EMBASE, and Web of Science were searched since inception to June 2022. Inclusion criteria were: (1) observational studies or surveys; (2) studies on patients with chronic diseases; (3) reporting the effects of COVID-19 pandemic on adherence to chronic pharmacological treatment, as a comparison of adherence during the pandemic period vs. pre-pandemic period (primary outcome) or as rate of treatment discontinuation/delay specifically due to factors linked to COVID-19 (secondary outcome). Findings from 12 (primary outcome) and 24 (secondary outcome) studies showed that many chronic treatments were interrupted or affected by a reduced adherence in the pandemic period, and that fear of infection, difficulty in reaching physicians or healthcare facilities, and unavailability of medication were often reported as reasons for discontinuation or modification of chronic therapies. For other therapies where the patient was not required to attend the clinic, continuity of treatment was sometimes ensured through the use of telemedicine, and the adherence was guaranteed with drug stockpiling. While the effects of the possible worsening of chronic disease management need to be monitored over time, positive strategies should be acknowledged, such as the implementation of e-health tools and the expanded role of community pharmacists, and may play an important role in preserving continuity of care for people with chronic diseases.

Beta-blockers in post-acute myocardial infarction patients: Drug prescription patterns from 2018 to Italy's first wave of the COVID-19 pandemic.

Background: Major guidelines recommend the initiation of a beta-blocker therapy after an acute myocardial infarction (AMI). We aimed to map the treatment pathway of beta-blockers for AMI survivors during the first wave of COVID-19 pandemic in Italy and to investigate predictors for treatment non-initiation. Methods: Healthcare utilization databases of Lombardy Region were investigated. Subjects aged ≥18 years who were hospitalised with AMI in the period February-March-April of 2018, 2019, and 2020 were included, and followed for 30 days from the discharge date, to investigate whether they presented a first prescription of beta-blockers. A multivariate logistic model was performed to evaluate the effect of several covariates on the probability of not receiving a post-AMI beta-blocker therapy. Results: The cohorts comprised 2259, 2383, and 1932 individuals who were hospitalised with AMI in the 3-month period in 2018, 2019, and 2020, respectively. Overall in 2020, about 58-60% of individuals with AMI received a prescription of beta-blockers within 1 month after the discharge. A continuous decreasing trend over time was observed. Men were 30% more likely to start the treatment than women, increasing age was associated with significant increasing probability of not receiving a post-infarction beta-blocker therapy, while having received an antihypertensive or lipid-lowering treatment, or having been hospitalized for heart failure prior to the AMI hospitalization reduced the likelihood of not being treated with beta-blockers. Conclusion: The initiation of beta-blocker treatment after AMI remains an under-prescribed practice, that does not seem to have been further affected by the first wave of the COVID-19 pandemic.

Impact of the COVID-19 Pandemic on the Therapeutic Continuity among Outpatients with Chronic Cardiovascular Therapies.

The COVID-19 pandemic poses major challenges to healthcare systems. We aimed to investigate the impact of the pandemic on prescription and adherence patterns of chronic cardiovascular therapies (lipid-lowering [LL], oral antidiabetic drugs [AD], and antihypertensives [AH]) using administrative pharmaceutical databases. For each treatment, two cohorts of prevalent cases in 2019 and 2020 were compared. We evaluated the percentage change in dispensed packages and treatment adherence as a proportion of days covered (PDC). For all therapies, an increase was observed during March-April 2020 (LL: +4.52%; AD: +2.72%; AH: +1.09%), with a sharp decrease in May-June 2020 (LL: -8.40%; AD: -12.09%; AH: -10.54%) compared to 2019. The impact of the COVID-19 pandemic on chronic cardiovascular treatments appears negligible on adherence: 533,414 patients showed high adherence to LL (PDC ≥ 80%) in January-February 2020, and 2.29% became poorly adherent (PDC < 20%) in the following four-month period (vs. 1.98% in 2019). A similar increase was also observed for AH (1.25% with poor adherence in 2020 vs. 0.93% in 2019). For AD, the increase was restrained (1.55% with poor adherence in 2020 vs. 1.37% in 2019). The rush to supply drugs at the beginning of lockdown preserved the continuity of chronic cardiovascular therapies.

Antibiotic Prescription in the Community-Dwelling Elderly Population in Lombardy, Italy: A Sub-Analysis of the EDU.RE.DRUG Study.

Inappropriate consumption and over-prescription of antibiotics have been extensively reported. Our aim was to specifically evaluate the antibiotic prescribing patterns and appropriateness among the elderly (≥65 years) from the Lombardy region (Italy) in primary care. Antibiotic consumption (as DID: DDD/1000 inhabitants × day) and prevalence rates in 2018 were assessed, and the prescribing quality was evaluated using ESAC-based indicators and WHO-AWaRe criteria. A multivariate logistic regression analysis was performed to evaluate the association between the probability of receiving an antibiotic prescription and patients' and physicians' characteristics. A total of 237,004 antibiotic users were included (mean age ± SD 75.98 ± 7.63; males 42.7%). Antibacterial consumption was equal to 17.2 DID, with values increasing with age in both males and females. The study found that the proportion of patients with at least one antibiotic prescription in 2018 was around 39.1%, with different age-related trends between males and females. Consumption (as DID) of cephalosporines (65-74 years: 1.65; 75-84 years: 2.06; ≥85 years: 2.86) and quinolones (3.88, 4.61, 4.96, respectively) increased with growing age, while consumption of penicillins (6.21, 6.08, 6.04, respectively) and macrolides, lincosamides, and streptogramins (3.25, 2.91, 2.64, respectively) decreased. In 2018, antibiotics considered to have higher toxicity concerns or resistance potential, as reported by WHO-AWaRe tool, were consumed more intensively than those to be used as first choices, independent of age and sex. The probability of receiving an antibiotic prescription was greater in females, in subjects with polypharmacy, in treatment with respiratory drugs, anti-inflammatory agents or glucocorticoids, and with previous hospitalization; but increasing age was less associated with exposition to antibiotics.

The Effectiveness of Interventions to Evaluate and Reduce Healthcare Costs of Potentially Inappropriate Prescriptions among the Older Adults: A Systematic Review.

Potentially inappropriate prescribing (PIP) is associated with an increased risk of adverse drug reactions, recognized as a determinant of adherence and increased healthcare costs. The study's aim was to explore and compare the results of interventions to reduce PIP and its impact on avoidable healthcare costs. A systematic literature review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement guidelines. PubMed and Embase were queried until February 2021. Inclusion criteria followed the PICO model: older patients receiving PIP; Interventions aimed at health professionals, structures, and patients; no/any intervention as a comparator; postintervention costs variations as outcomes. The search strategy produced 274 potentially relevant publications, of which 18 articles met inclusion criteria. Two subgroups were analyzed according to the study design: observational studies assessing PIP frequency and related-avoidable costs (n = 10) and trials, including specific intervention and related outcomes in terms of postintervention effectiveness and avoided costs (n = 8). PIP prevalence ranged from 21 to 79%. Few educational interventions carried out to reduce PIP prevalence and avoidable costs resulted in a slowly improving prescribing practice but not cost effective. Implementing cost-effective strategies for reducing PIP and clinical and economic implications is fundamental to reducing health systems' PIP burden.

Evaluation of Factors Associated With Appropriate Drug Prescription and Effectiveness of Informative and Educational Interventions-The EDU.RE.DRUG Project.

Background: EDU.RE.DRUG study is a prospective, multicentre, open-label, parallel-arm, controlled, pragmatic trial directed to general practitioners (GPs) and their patients. Methods: The study data were retrieved from health-related administrative databases of four local health units (LHUs) of Lombardy and four LHUs in Campania. According to the LHUs, the GPs/patients were assigned to (A) intervention on both GPs (feedback reports about appropriate prescribing among their patients and online courses) and patients (flyers and posters on proper drug use), (B) intervention on GPs, (C) intervention on patients, and (D) no intervention (control arm). A set of appropriate prescribing indicators (potential drug-drug interactions [pDDIs], potential and unnecessary therapeutic duplicates [pTDs], and inappropriate prescriptions in the elderly [ERD-list]) were measured at baseline and after the intervention phase. The effectiveness of the intervention was evaluated estimating the absolute difference in percentages of selected indicators carrying out linear random-intercept mixed-effect models. Results: A cohort of 3,586 GPs (2,567 in intervention groups and 1,019 in the control group) was evaluated. In Campania, the mean pre-intervention percentage of patients with at least one pDDI was always greater than 20% and always lower than 15% in Lombardy. The pre-post difference was quite heterogeneous among the LHUs, ranging from 1.9 to -1.4 percentage points. The mean pre-intervention percentage of patients with pTDs ranged from 0.59 to 2.1%, with slightly higher values characterizing Campania LHUs. The magnitude of the pre-post difference was very low, ranging from -0.11 to 0.20. In Campania, the mean pre-intervention percentage of patients with at least one ERD criterium was considerably higher than in Lombardy (approximately 30% in Lombardy and 50% in Campania). The pre-post difference was again quite heterogeneous. The results from the models accounting for GP geographical belonging suggested that none of the interventions resulted in a statistically significant effect, for all the three indicators considered. Conclusion: The proposed strategy was shown to be not effective in influencing the voluntary changes in GP prescription performance. However, the use of a set of explicit indicators proved to be useful in quantifying the inappropriateness. Further efforts are needed to find more efficient strategies and design more tailored interventions.

Potentially Inappropriate Prescribing among Elderly Outpatients: Evaluation of Temporal Trends 2012-2018 in Piedmont, Italy.

Pharmacological intervention is one of the cornerstones in the treatment and prevention of disease in modern healthcare. However, a large number of drugs are often prescribed and used inappropriately, especially in elderly patients. We aimed at investigating the annual prevalence of potentially inappropriate prescriptions (PIPs) among older outpatients using administrative healthcare databases of the Piedmont Region (Italy) over a seven-year period (2012-2018). We included all Piedmont outpatients aged 65 years or older with at least one drug prescription per year. Polypharmacy and the prevalence of PIPs according to the ERD list explicit tool were measured on an annual basis. A range between 976,398 (in 2012) and 1,066,389 (in 2018) elderly were evaluated. Among them, the number of subjects with at least one PIP decreased from 418,537 in 2012 to 339,764 in 2018; the prevalence significantly reduced by ~25% over the study period. The stratified analyses by age groups and sex also confirmed the downward trend and identified several differences in the most prevalent inappropriately prescribed drugs. Overall, despite a reduction in PIP prevalence, one out of three older outpatients was still exposed to inappropriateness, highlighting the extensive need for intervention to improve prescribing.

Reduction of Cardio-Metabolic Risk and Body Weight through a Multiphasic Very-Low Calorie Ketogenic Diet Program in Women with Overweight/Obesity: A Study in a Real-World Setting.

BACKGROUND: The prevention and treatment of obesity and its cardio-metabolic complications are relevant issues worldwide. Among lifestyle approaches, very low-calorie ketogenic diets (VLCKD) have been shown to lead to rapid initial weight loss, resulting in better long-term weight loss maintenance. As no information on VLCKD studies carried on in a real-world setting are available, we conducted this multi-centre study in a real-world setting, aiming at assessing the efficacy and the safety of a specific multiphasic VLCKD program in women with overweight or obesity. METHODS: A multi-center, prospective, uncontrolled trial was conducted in 33 outpatient women (age range 27-60 y) with overweight or obesity (BMI: 30.9 ± 2.7 kg/m2; waist circumference: 96.0 ± 9.4 cm) who started a VLCKD dietary program (duration: 24 weeks), divided into four phases. The efficacy of VLCKD was assessed by evaluating anthropometric measures and cardiometabolic markers; liver and kidney function biomarkers were assessed as safety parameters. RESULTS: The VLCKD program resulted in a significant decrease of body weight and BMI (-14.6%) and waist circumference (-12.4%). At the end of the protocol, 33.3% of the participants reached a normal weight and the subjects in the obesity range were reduced from 70% to 16.7%. HOMA-IR was markedly reduced from 3.17 ± 2.67 to 1.73 ± 1.23 already after phase 2 and was unchanged thereafter. Systolic blood pressure decreased after phase 1 (-3.5 mmHg) and remained unchanged until the end of the program. Total and LDL cholesterol and triglycerides were significantly reduced by VLCKD along with a significant HDL cholesterol increase. Liver, kidney and thyroid function markers did not change and remained within the reference range. CONCLUSIONS: The findings of a multi-center VLCKD program conducted in a real-world setting in a cohort of overweight/obese women indicate that it is safe and effective, as it results in a major improvement of cardiometabolic parameters, thus leading to benefits that span well beyond the mere body weight/adiposity reduction.

Geographical Variation in Medication Prescriptions: A Multiregional Drug-Utilization Study.

BACKGROUND: Studies have emphasized the importance of geographical factors and general practitioner (GP) characteristics in influencing drug prescriptions. OBJECTIVES: To: (i) ascertain the prevalence rate (PR) of use of drugs in six therapeutic categories used for chronic conditions; (ii) assess how geographical characteristics and GP characteristics may influence drug prescribing. METHODS: This study is part of the EDU.RE.DRUG Project, a national collaborative project founded by Italian Medicine Agency (AIFA). Cross-sectional analyses were undertaken employing the pharmacy-claim databases of four local health units (LHUs) located in two Italian regions: Lombardy and Campania. Six drug categories were evaluated: proton-pump inhibitors; antibiotics; respiratory-system drugs; statins; agents acting on the renin-angiotensin system; psychoanaleptic drugs. The PR was estimated according to drug categories at the LHU level. A linear multivariate regression analysis was undertaken to evaluate the association between the PR and geographical area, age and sex of GPs, number of patients, and percentage of patients aged >65 per GP. RESULTS: LHUs in Campania showed a PR that was significantly higher than that in Lombardy. Antibiotics showed the highest PR in all the LHUs assessed, ranging from 32.5% in Lecco (Lombardy) to 59.7% in Naples-2 (Campania). Multivariate linear regression analysis confirmed the association of the PR with geographical area for all drug categories. Being located in Campania increased the possibility of receiving a drug prescription from the categories considered, with estimates more marked for antibiotics, proton-pump-inhibitors, and respiratory-system drugs. CONCLUSIONS: This study provides information about the PR of medications used for treating common and costly conditions in Italy and highlighted a significant geographical variation. These insights could help to develop area-specific strategies to optimize prescribing behavior.

Association between the cumulative exposure to bisphosphonates and hospitalization for atherosclerotic cardiovascular events: A population-based study.

BACKGROUND AND AIMS: Although bisphosphonates have been suggested to protect against atherosclerotic cardiovascular (CV) events, evidence is still conflicting. We aimed at investigating the effect of bisphosphonates on hospitalizations for atherosclerotic CV events. METHODS: We carried out a retrospective cohort study selecting subjects aged>40 years, incident users of bisphosphonates. Exposure to bisphosphonates was characterized based on cumulative doses (proportion of days covered, PDC). Treatment's adherence was classified as low (PDC≤40%), intermediate (PDC 41%-80%), or high (PDC>80%). A multivariate Cox model was fitted to estimate the association between cumulative time-dependent exposure to bisphosphonates and hospitalization for atherosclerotic CV events (hazard ratio [HR] and 95% confidence interval). RESULTS: Among 82,704 new bisphosphonates users (females 87.0%, mean age 70.7 ± 10.6 years), 16.1% had a CV hospitalization during a mean follow-up of 6.5 + 2.6 years. Compared with individuals with PDC ≤40%, those exposed for 41-80% or more than 80% showed HRs of CV hospitalization of 0.95 [0.91-0.99] and 0.75 [0.71-0.81], respectively. In the sub-analysis by type of event, a PDC >80% was associated with a reduced incidence for both coronary and cerebrovascular events (HRs 0.75 [0.68-0.83] and 0.76 [0.70-0.83], respectively). The protective effect was confirmed in stratified analyses by sex and age classes, and in those performed at 1 and 3 years of follow-up. CONCLUSIONS: Strict adherence to bisphosphonate treatment was associated with a better CV outcome. Although further studies to investigate possible mechanisms are warranted, bisphosphonates could be considered as having a potential CV benefit beyond the effect on bones.

Sex-differences in factors and outcomes associated with adherence to statin therapy in primary care: Need for customisation strategies.

Despite the invaluable efficacy of statins, adherence to therapy is extremely poor in clinical practice. Improvement interventions should be as personalized as possible, but it is necessary to know factors that most influence adherence, and sex seems to be a key determinant. Thus, we aimed at exploring potential areas of sex-differences in statin adherence in a real-world population. For this purpose, we assessed adherence (as proportion of days covered) on a wide cohort of new statin users aged >40 years, and we evaluated its association with several covariates through sex-stratified log-binomial regression models. In addition, to compare also the benefits of optimal statin adherence in primary prevention of cardiovascular disease between men and women, we implemented sex-stratified Cox proportional hazard models. Our study showed that women are more likely to stop or be less adherent to statin treatment than men. Moreover, we observed significant sex-differences on effect size of several factors associated with adherence that should be taken into consideration for the management of patients. Finally, we observed no significant difference between men and women regarding statin efficacy in terms of reduction of incident hospitalization for ischemic heart disease and/or non-haemorrhagic cerebrovascular disease. These results invoke the responsibility of physicians to a prompt and personalized intervention. Physicians should consider routine screening for non-adherence in their clinical practice, target patients at higher risk of non-adherence, and improved motivation and communication.

Prevalence and relationship between metabolic syndrome and risk of cardiovascular disease: Evidence from two population-based studies.

BACKGROUND AND AIM: The metabolic syndrome (MetS) has become one of the most important clinical issues in the cardiovascular field for this decade because of the marked increase in cardiovascular (CV) risk associated with a clustering of risk factors. The aim of the current study was to evaluate the relationship between MetS and its components and cardiovascular disease (CVD). METHODS: This population-based cross-sectional study was based on data from two studies carried out in Russia (ESSE-RF) and Italy (PLIC). One sample from each cohort was selected, matching individuals by sex and age. A comparison between samples of MetS components distribution and CV risk, according to SCORE chart, has been conducted. RESULTS: A total of 609 individuals (mean [SD] age 55 [8] years, about 39% males) for each cohort were selected. Almost half of PLIC cohort participants belonged to the moderate CV risk group (47% vs 27%), while in ESSE-RF cohort a relatively higher prevalence of individuals classified in the high and very high risk group was observed (19% vs 11%, 21% vs 6%, respectively). Overall, 43% of ESSE-RF participants were diagnosed with MetS, compared with the 27% of PLIC members (the difference in prevalence becomes 37% vs 21%, considering a more conservative cut-off for waist circumference). Both cohorts showed a trend towards the increase of MetS components moving from the lowest to the highest CV risk class, with a high prevalence of patients with four or five MetS determinants allocated in the high/very high CV risk group. CONCLUSIONS: Developing effective public health strategies for the prevention, detection and treatment of MetS should be an urgent priority to reduce the burden of CVD, not only in subjects at high/very high CV risk, but also in those characterized by a lower risk, as even rare CV events that come from low risk group bring a tangible burden to healthcare systems.

Multilevel Models to Estimate Carotid Intima-Media Thickness Curves for Individual Cardiovascular Risk Evaluation.

Background and Purpose- The value of carotid intima-media thickness (cIMT)-a marker of subclinical atherosclerosis-in defining the cardiovascular risk is still debated. The aim of this study was to estimate standard cIMT progression, adjusting values over time for the main cardiovascular risk factors, in a sample of low-to-moderate cardiovascular risk subjects, to identify normative cIMT progression values. Methods- From the progression of lesions in the intima of the carotid cohort, we selected subjects who underwent 4 planned serial clinical evaluations and ultrasound cIMT determinations, on average every 4 years. Subject taking glucose-lowering therapies in secondary cardiovascular prevention or with cardiovascular risk score >5 were excluded from the analysis. The growth of cIMT across the study period (12 years) was assessed by use of individual growth curve modeling within multilevel models. Results- A total of 1175 (36% men; mean age, 53±11 years at baseline) participants at low/intermediate cardiovascular risk have been included in this analysis. A significant and marked slope of the mean and maximum cIMT growth curves (ß=0.009 and ß=0.012, respectively) was observed, confirming that it is a function of age. A stratified analysis by decades of age highlighted a nonlinear cIMT progression over time. In addition, different patterns of cIMT development between sex were observed. Finally, different slopes in mean and maximum cIMT curves, with a significant spread since the fifth decade, were observed in the cIMT growth curve models of subjects developing multifocal carotid atherosclerosis compared with the rest of the population. Conclusions- These findings proved that the rate of change in cIMT over time is a sign of the development of atherosclerosis, which cannot be a priori assumed linear. These data, therefore, support the clinical relevance of these growth curve models for cIMT progression to be considered as useful tool to identify subjects with faster atherosclerosis progression and thus at increased cardiovascular risk.

Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials.

The therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors efficiently reduces plasma cholesterol levels, which has been recently associated with improvement in cardiovascular outcomes. This meta-analysis aimed at investigating the safety and efficacy of treatment with the clinically available anti-PCSK9 monoclonal antibodies (mAbs) in all published randomized clinical trials (RCTs), updating the available results with the recently published ODYSSEY OUTCOMES trial. Data search was carried out using PubMed/MEDLINE and EMBASE (inception - January 2019). Inclusion criteria were: (1) phase 2 or 3 RCTs; (2) comparing anti-PCSK9 mAbs (specifically evolocumab and alirocumab) with placebo; (3) with effects on outcomes reported; (4) with treatment duration longer than 8 weeks. Odds ratios (ORs) with 95% CIs were used as summary statistics. We pooled the estimates by using both the DerSimonian & Laird method (random-effects model). Between-study heterogeneity was tested by Cochrane's Q test and measured with the I2 statistics. Twenty-eight RCTs comprising 62,281 participants (33,204 in the mAb arm, 29,077 in the placebo arm) were included in the meta-analysis. The treatment follow-up ranged from 8 weeks up to 208 weeks. Overall, no significant difference in all-cause mortality was observed between the two groups (OR 0.93 [95% CI, 0.85-1.03]). The treatment with an anti-PCSK9 mAb was associated with a significant reduction of CV events compared with placebo (OR 0.83 [95% CI, 0.78-0.87]), being the FOURIER and ODYSSEY OUTCOMES studies the major contributors. Both myocardial infarction and stroke were significantly reduced following the treatment with an anti-PCSK9 mAb. No significant difference was observed in cardiovascular mortality (OR 0.94 [95% CI, 0.83-1.07]). The incidence of serious adverse events was similar in the two groups (OR: 0.95, [95% CI, 0.91-0.99]). Thus, the pharmacological approach with anti-PCSK9 mAbs significantly and safely improves cardiovascular outcomes. Despite that, the pooled analysis failed to show a significant cardiovascular mortality benefit with anti-PCSK9 mAb treatment, suggesting that specific longer-term studies are warranted to address this issue. We suggest that the observed delay between the rapid effect on plasma cholesterol levels and the emergence of the clinical benefit, observed both in FOURIER and ODYSSEY OUTCOMES trials, might explain this finding.

Epidemiology of cardiovascular risk factors in two population-based studies.

We aimed to compare cardiovascular risk factors prevalence in Italy and Russia through cross-sectional database analysis. The study has been based on data from ESSE-RF and from baseline of PLIC study, two population-based epidemiological studies aimed to investigate prevalence of risk factors and evaluating contribution of traditional and new risk factors into morbidity and cardiovascular mortality. A total of 2203 patients with left and right intima-media thickness (IMT) measurements constituted the source population (1205 from PLIC study and 998 from ESSE-RF study). Sample of ESSE-RF study had slightly more diabetic and hypertensive individuals, while the percentage of subjects with high cholesterol value was lower than in the other sample (67.1% vs 79.9%). The median LDL-C value was higher among individuals not treated with statins in the PLIC sample (p < 0.001), while was comparable among subjects receiving statin therapy. On the other hand, the percentage of individuals with positive cardiovascular history was higher in ESSE-RF sample. This could also explain the higher mean IMT value (0.71 ±â€¯0.17 vs 0.63 ±â€¯0.13) in the whole sample, and among patients without past cardiovascular events (regardless of statin treatment), despite some differences in major risk factors. Despite Russian and Italian populations are culturally and geographically different, they are not so different based on characteristics analyzed.

Use of proton pump inhibitors and risk of ischemic events in the general population.

BACKGROUND AND AIMS: A potential increased risk of cardiovascular events has been suggested for proton pump inhibitors (PPIs), the most commonly prescribed drugs for the management of upper gastrointestinal disorders. We aimed to estimate the risk of hospitalization for cardio/cerebrovascular (CV) events in a cohort of incident PPI users. METHODS: A nested case-control study was carried out using regional healthcare utilization databases. For each case (hospitalization for non-haemorrhagic CV event), up-to-five controls randomly selected from the cohort were matched by gender, age at cohort entry, and index date. Exposure was estimated as recency of therapy (current, recent and past users) and number of days covered. Adjusted conditional logistic regression was used to estimate the association between exposure and outcome. RESULTS: Among new PPI users, we identified 17,832 cases and 89,160 controls (males 64.9%; mean age 58.9 years). Cases showed a significantly higher prevalence of use of drugs for diabetes, hypertension and hypercholesterolemia than controls. Risk of CV events was significantly higher for current (OR 1.61; 95%CI 1.55-1.68) and recent users (OR 1.15; 95%CI 1.06-1.26) compared to past users. Analogous results were found stratifying for cardiovascular (ORcurrent 1.71; 95%CI 1.63-1.81) and cerebrovascular events (ORcurrent 1.43; 95%CI 1.34-1.54). The increased risk was confirmed in subgroups by antithrombotic, statin use, or exposure duration. The same analysis for H2-antagonists use showed no significant results. CONCLUSIONS: In primary care setting, PPI use was independently associated with increased risk of first-time cardiovascular event, consistent with the evidence that PPIs adversely impact vascular function, underlying the need to promote appropriate prescribing of these drugs.

Tools to investigate and avoid drug-hypersensitivity in drug development.

INTRODUCTION: Drug hypersensitivity reactions (DHRs) are common adverse effects of pharmaceuticals that clinically resemble allergies, and which are becoming an important burden to healthcare systems. Alongside accurate diagnostic techniques, tools which can predict potential drug-inducing hypersensitivity reactions in the pre-clinical phase are critical. Despite the important adverse reactions linked to immune-mediated hypersensitivity, at present, there are no validated or required in vivo or in vitro methods to screen the sensitizing potential of drugs and their metabolites in the pre-clinical phase. Areas covered: Enhanced prediction in preclinical safety evaluation is extremely important. The purpose of this review is to assess the state of the art of tools available to assess the allergenic potential of drugs and to highlight our current understanding of the molecular mechanisms underlying inappropriate immune activation. Expert opinion: The knowledge that allergenic drugs share common mechanisms of immune cell activation with chemical allergens, and of the definition of the mechanistic pathway to adverse outcomes, can enhance targeting toxicity testing in drug development and hazard assessment of hypersensitivity. Additional efforts and extensive resources are necessary to improve preclinical testing methodologies, including optimization, better design and interpretation of data.

Drug treatment and adherence of subjects <40 years with diagnosis of heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS: We aimed at describing the therapeutic approach in young adult patients diagnosed with heterozygous familial hypercholesterolemia (HeFH) and their adherence and persistence to treatment. METHODS: From regional administrative databases, individuals aged ≤40 years, who received exemption for HeFH between January 1, 2003 and December 31, 2011, and concomitantly started statin treatment, were identified. Within the first year of treatment, we evaluated therapeutic changes, adherence as MPR (medication possession ratio), persistence as continuous drug coverage without gaps ≥60 days, and influencing factors using log binomial models. RESULTS: Of 1404 patients, 42.4% were initially treated with a high-efficacy statin. 23.4% of patients showed at least one treatment change. Mean MPR was 68.7% (29.9), and patients showing continued statin use were 47.0%. Therapy modification was significantly associated with a past cardiovascular event (relative risk, RR [95% confidential interval] 2.28 [1.69-3.09]) and at least one lipid test (RR 1.82 [1.31-2.53]). MPR ≥80% was significantly associated with the first statin prescribed (atorvastatin RR 1.28 [1.09-1.51] and rosuvastatin RR 1.21 [1.01-1.44], vs. simvastatin), a past cardiovascular event (RR 1.33 [1.12-1.59]), at least one therapy change (RR 1.28 [1.15-1.43]), at least a lipid test (RR 1.26 [1.07-1.49]). A similar pattern was observed for persistence. CONCLUSIONS: This analysis of young adult HeFH patients showed that therapy change was quite frequent, and probably reflected adjustments according to individual response. Adherence and persistence were inadequate, even in this population at high cardiovascular risk, and they need to be improved through proper patient education and shared treatment decision-making approach.