Emanuel Raschi

Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis

Objective To quantify the risk of hypoglycaemia associated with the concomitant use of dipeptidyl peptidase-4 (DPP-4) inhibitors and sulphonylureas compared with placebo and sulphonylureas. Design Systematic review and meta-analysis. Data sources Medline, ISI Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, and clinicaltrial.gov were searched without any language restriction. Study selection Placebo controlled randomised trials comprising at least 50 participants with type 2 diabetes treated with DPP-4 inhibitors and sulphonylureas. Review methods Risk of bias in each trial was assessed using the Cochrane Collaboration tool. The risk ratio of hypoglycaemia with 95% confidence intervals was computed for each study and then pooled using fixed effect models (Mantel Haenszel method) or random effect models, when appropriate. Subgroup analyses were also performed (eg, dose of DPP-4 inhibitors). The number needed to harm (NNH) was estimated according to treatment duration. Results 10 studies were included, representing a total of 6546 participants (4020 received DPP-4 inhibitors plus sulphonylureas, 2526 placebo plus sulphonylureas). The risk ratio of hypoglycaemia was 1.52 (95% confidence interval 1.29 to 1.80). The NNH was 17 (95% confidence interval 11 to 30) for a treatment duration of six months or less, 15 (9 to 26) for 6.1 to 12 months, and 8 (5 to 15) for more than one year. In subgroup analysis, no difference was found between full and low doses of DPP-4 inhibitors: the risk ratio related to full dose DPP-4 inhibitors was 1.66 (1.34 to 2.06), whereas the increased risk ratio related to low dose DPP-4 inhibitors did not reach statistical significance (1.33, 0.92 to 1.94). Conclusions Addition of DPP-4 inhibitors to sulphonylurea to treat people with type 2 diabetes is associated with a 50% increased risk of hypoglycaemia and to one excess case of hypoglycaemia for every 17 patients in the first six months of treatment. This highlights the need to respect recommendations for a decrease in sulphonylureas dose when initiating DPP-4 inhibitors and to assess the effectiveness of this risk minimisation strategy.

Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System

BACKGROUND AND AIMSnWe tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS).nnnMETHODSnFAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query Cardiac failure. Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders.nnnRESULTSnHF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (RORxa0=xa01.17; 95% CIxa0=xa01.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant.nnnCONCLUSIONnFAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved.

Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system

AIMS Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well‐known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO‐UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO‐Vigibase was also queried. RESULTS From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO‐Vigibase. CONCLUSIONS The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.

Drug-induced liver injury: Towards early prediction and risk stratification

Drug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications and agents listed as causing liver damage (http://livertox.nih.gov/). As it was the case in the past decade with drug-induced QT prolongation/arrhythmia, there is an urgent unmet clinical need to develop tools for risk assessment and stratification in clinical practice and, in parallel, to improve prediction of pre-clinical models to support regulatory steps and facilitate early detection of liver-specific adverse drug events. Although drug discontinuation and therapy reconciliation still remain the mainstay in patient management to minimize occurrence of DILI, especially acute liver failure events, different multidisciplinary attempts have been proposed in 2016 to predict and assess drug-related risk in individual patients; these promising, albeit preliminary, results strongly support the need to pursue this innovative pathway.

Risk–Benefit Profile of Direct-Acting Oral Anticoagulants in Established Therapeutic Indications: An Overview of Systematic Reviews and Observational Studies

Since 2008, the direct-acting oral anticoagulants (DOACs) have expanded the therapeutic options of cardiovascular diseases with recognized clinical and epidemiological impact, such as non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), and also in the preventive setting of orthopedic surgical patients. The large body of evidence, not only from pivotal clinical trials but also from ‘real-world’ postmarketing observational findings (e.g. analytical epidemiological studies and registry data) gathered to date allow for a first attempt at verifying a posteriori whether or not the pharmacological advantages of the DOACs actually translate into therapeutic innovation, with relevant implications for clinicians, regulators and patients. This review aims to synthesize the risk–benefit profile of DOACs in the aforementioned consolidated indications through an ‘evidence summary’ approach gathering the existent evidence-based data, particularly systematic reviews with meta-analyses of randomized controlled trials, as well as observational studies, comparing DOACs with vitamin K antagonists. Clinical evidence will be discussed and compared with major international guidelines to identify whether an update is needed. Controversial clinically relevant safety issues will be also examined in order to highlight current challenges and unsettled questions (e.g. actual bleeding risk in susceptible populations). It is anticipated that the large number of publications on NVAF or VTE (44 systematic reviews with meta-analyses and 12 observational studies retained in our analysis) suggests the potential existence of overlapping studies and calls for common criteria to qualitatively and quantitatively assess discordances, thus guiding future research.

Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: Beyond bleeding complications

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered thexa0market in 2008 with the expected breakthrough potential of circumventing limitations related to treatmentxa0with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although dataxa0derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit ofxa0DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safetyxa0in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy,xa0in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluatexa0the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need forxa0pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding,xa0and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) thexa0importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section,xa0emerging and debated safety issues potentially associated with the use of DOACs in the postmarketingxa0setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period);xa02) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports orxa0series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepaticxa0and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.

Appropriateness of Proton Pump Inhibitor (PPI) prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy

INTRODUCTIONnProton pump inhibitor (PPI) prescriptions have raised concern for both huge increase of health expenditure and possible long-term adverse effects.nnnOBJECTIVEnTo evaluate appropriateness of PPI prescription in ambulatory and hospital care.nnnDESIGNnObservational cohort study.nnnPATIENTSnPatients admitted to the Internal Medicine Unit of Bologna S. Orsola Hospital between 15/09/2013 and 15/12/2013. Data on clinical condition and drug therapy were collected at three time points: admission (reflecting GPs prescription), hospital stay and discharge.nnnMAIN MEASURESnAppropriateness of PPI use was evaluated as follows: (1) agreement between PPI use/non-use and appropriate clinical condition; (2) in PPI users, assessment of Medication Appropriateness Index (MAI). Differences in appropriateness among time points were analyzed by chi-square test. Logistic regression model was used to identify possible determinants of PPI appropriateness.nnnKEY RESULTSnAmong 280 patients, 56% received PPI at least once in the three time points. Appropriateness, according to indication of use, was similar between admission and hospital stay (61% vs. 62%; p=0.82) and between hospital stay and discharge (62% vs. 59%; p=0.94). MAI score showed important, although statistically non-significant, change in appropriateness between admission and hospital stay (20% vs. 28%; p=0.16). Age≥65 was always associated with appropriate PPI use (up to OR=4.37; p<0.01), whereas cardiovascular comorbidity and conditions requiring analgesic treatment influenced appropriateness only at admission (OR=3.84; p<0.01 and OR=0.34; p<0.01, respectively).nnnCONCLUSIONSnHospital clinicians only rarely reconsidered GPs choice to prescribe PPI. Room for improvement in PPI appropriateness is represented by (1) assessing gastrointestinal risk in each patient under analgesics and anti-inflammatory drugs, and (2) short-term re-evaluation of PPI prescription after discharge.

Emerging therapeutic uses of direct-acting oral anticoagulants: An evidence-based perspective

&NA; Direct‐acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short‐ and long‐term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre‐approval pivotal trials to real‐world post‐marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin‐K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non‐valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk‐benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin‐induced thrombocytopenia, anti‐phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories. Graphical abstract Figure. No caption available.

Drug-Induced Arrhythmia: Bridging the Gap Between Pathophysiological Knowledge and Clinical Practice

In this issue, Woosley et al. [1] describe an important tool for use in clinical decision making about drugs associated with a risk of Torsades de pointes (TdP), a life-threatening ventricular tachyarrhythmia specifically defined by its characteristic electrocardiographic (ECG) profile. Their work is particularly useful for clinicians and patients because drugs are assigned to categories according to their risk of TdP via the integrated approach, ‘‘Adverse Drug Event Causality Analysis’’ (ADECA). This approach combines updated information from published and unpublished data (mainly disproportionality analysis of major international spontaneous reporting systems). ‘‘CredibleMeds.org’’ is a website through which it is possible to freely (only registration required) view categories of drugs with torsadogenic potential: known TdP risk, possible TdP risk, conditional TdP risk, and drugs to be avoided in patients with long QT syndrome. TdP is a well-described clinical condition, known as a designated medical event in pharmacovigilance. It is typically associated with QT prolongation and can lead to sudden cardiac death (SCD) when it degenerates into ventricular fibrillation [2]. However, as the spectrum of events is seldom observed in its entirety, the diagnosis can only be guessed, not proved, in many cases (e.g., in a patient with SCD a few days after starting a new drug). QT prolongation is relatively common and is a prerequisite for TdP, whereas TdP itself is very rare. The important gap in knowledge relates to how the two are linked. Moreover, drugs such as verapamil can cause QT prolongation with minimal or no observed cases of TdP. Thus, this is a grey area in which a surrogate marker of toxicity (QT prolongation) is extensively documented and largely used by regulators during drug development, but assessing the actual risk of TdP in a single patient is difficult. A tool to assist in clinical decision making is particularly important in areas such as this.

Drug-induced renal injury in neonates: Challenges in clinical practice and perspectives in drug development.

ABSTRACT Introduction: Acute kidney injury (AKI) is frequently diagnosed in the neonatal population, especially in those admitted to intensive care units, and poses several challenges for clinicians mainly because of difficulties in timely identification of renal impairment and the need to administer drugs with potential nephrotoxicity. In this context, research on biomarkers is growing for their implication in the early detection of renal damage and their higher sensitivity in monitoring renal activity, but also as an important tool for drug development. Areas covered: We described the tools currently used to detect renal damage in neonatal settings, their limits and applicability, as well as the role of drugs on renal toxicity occurrence. Subsequently, we discuss current knowledge on new biomarkers for the detection of kidney injury and drug-induced kidney injury in neonates, and the qualification programs developed by regulatory agencies for biomarkers intended as tools in drug development. Expert opinion: Some molecules are emerging as potential biomarkers for early detection of AKI: promising data has demonstrated higher sensitivity and accuracy compared with tools currently used in the clinical setting. In addition, novel techniques (e.g. high power magnetic resonance imaging) to assess long-term consequences of AKI in neonates are in early steps of development.