The safety and efficacy of Avanafil, a new 2^nd generation PDE5i: comprehensive review and meta-analysis

<p><b><i>Introduction</i>:</b> The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. Recently, a new PDE5ì, avanafil, has become available worldwide.</p> <p><b><i>Areas covered</i>:</b> All placebo-controlled randomized clinical trials (RCTs) on the effect of avanafil in patients with ED were reviewed and meta-analyzed. So far, 5 different RCTs on avanafil have been published, including 1379 and 605 patients in active and placebo groups, respectively. Avanafil was up to 3-fold superior to placebo in determining successful sexual intercourse. Although head-to-head comparative studies are still lacking, re-analyses of available data, showed that avanafil had comparable efficacy, but lower incidence of drug-related side effects, compared to first-generation PDE5is.</p> <p><b><i>Expert opinion</i>:</b> Avanafil specific and peculiar pharmacological profile, addresses several problems that have been documented with first-generation PDE5is. Avanafil should theoretically guarantee a low dropout incidence by ensuring a natural profile of action and a low incidence of side effects. Longer studies and head-to-heard trials are advisable to clarify these issues.</p

Hyponatremia Improvement Is Associated with a Reduced Risk of Mortality: Evidence from a Meta-Analysis

<div><p>Background</p><p>Hyponatremia is the most common electrolyte disorder and it is associated with increased morbidity and mortality. However, there is no clear demonstration that the improvement of serum sodium concentration ([Na⁺]) counteracts the increased risk of mortality associated with hyponatremia. Thus, we performed a meta-analysis that included the published studies that addressed the effect of hyponatremia improvement on mortality.</p><p>Methods and Findings</p><p>A Medline, Embase and Cochrane search was performed to retrieve all English-language studies of human subjects published up to June 30^th 2014, using the following words: “hyponatremia”, “hyponatraemia”, “mortality”, “morbidity” and “sodium”. Fifteen studies satisfied inclusion criteria encompassing a total of 13,816 patients. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all fifteen studies, any improvement of hyponatremia was associated with a reduced risk of overall mortality (OR=0.57[0.40-0.81]). The association was even stronger when only those studies (n=8) reporting a threshold for serum [Na⁺] improvement to >130 mmol/L were considered (OR=0.51[0.31-0.86]). The reduced mortality rate persisted at follow-up (OR=0.55[0.36-0.84] at 12 months). Meta-regression analyses showed that the reduced mortality associated with hyponatremia improvement was more evident in older subjects and in those with lower serum [Na⁺] at enrollment.</p><p>Conclusions</p><p>This meta-analysis documents for the first time that improvement in serum [Na⁺] in hyponatremic patients is associated with a reduction of overall mortality.</p></div

Trial flow diagram.

<p>Trial flow diagram.</p

Odds ratio for overall mortality rate in patients from studies in which a threshold for serum [Na⁺] improvement >130 mmol/L was reported.

<p>Odds ratio for overall mortality rate in patients from studies in which a threshold for serum [Na⁺] improvement >130 mmol/L was reported.</p

Observational studies included in the meta-analysis.

<p>* = threshold for serum [Na⁺] improvement <u>></u>130 mmol/L.</p><p>HN: hyponatremia; HF: heart failure; SCLC: small cell lung cancer; APE: acute pulmonary embolism; MI; myocardial infarction.</p><p>Observational studies included in the meta-analysis.</p

Studies that met inclusion criteria but did not provide data for meta-analysis.

<p>Studies that met inclusion criteria but did not provide data for meta-analysis.</p

The metabolic role of prolactin: systematic review, meta-analysis and preclinical considerations

Hyperprolactinemia has been proven to induce hypogonadism and metabolic derangements in both genders, while the consequences of prolactin (PRL) deficiency have been poorly investigated. To systematically review and analyze data from clinical studies focusing on the metabolic consequences of abnormally high prolactin levels (HPRL) and low prolactin levels (LPRL). In addition, data from preclinical studies about underlying pathophysiological mechanisms were summarized and discussed. PRL contributes to providing the correct amount of energy to support the mother and the fetus/offspring during pregnancy and lactation, but it also has a homeostatic role. Pathological PRL elevation beyond these physiological conditions, but also its reduction, impairs metabolism and body composition in both genders, increasing the risk of diabetes and cardiovascular events. Hence, hypoprolactinemia should be avoided as much as possible during treatment with dopamine agonists for prolactinomas. Patients with hypoprolactinemia, because of endogenous or iatrogenic conditions, deserve, as those with hyperprolactinemia, careful metabolic assessment.</p

Moderate Hyponatremia Is Associated with Increased Risk of Mortality: Evidence from a Meta-Analysis

<div><p>Background</p><p>Hyponatremia is the most common electrolyte disorder in clinical practice, and evidence to date indicates that severe hyponatremia is associated with increased morbidity and mortality. The aim of our study was to perform a meta-analysis that included the published studies that compared mortality rates in subjects with or without hyponatremia of any degree.</p><p>Methods and Findings</p><p>An extensive Medline, Embase and Cochrane search was performed to retrieve the studies published up to October 1^st 2012, using the following words: “hyponatremia” and “mortality”. Eighty-one studies satisfied inclusion criteria encompassing a total of 850222 patients, of whom 17.4% were hyponatremic. The identification of relevant abstracts, the selection of studies and the subsequent data extraction were performed independently by two of the authors, and conflicts resolved by a third investigator. Across all 81 studies, hyponatremia was significantly associated with an increased risk of overall mortality (RR = 2.60[2.31–2.93]). Hyponatremia was also associated with an increased risk of mortality in patients with myocardial infarction (RR = 2.83[2.23–3.58]), heart failure (RR = 2.47[2.09–2.92]), cirrhosis (RR = 3.34[1.91–5.83]), pulmonary infections (RR = 2.49[1.44–4.30]), mixed diseases (RR = 2.59[1.97–3.40]), and in hospitalized patients (RR = 2.48[2.09–2.95]). A mean difference of serum [Na⁺] of 4.8 mmol/L was found in subjects who died compared to survivors (130.1±5.6 <i>vs</i> 134.9±5.1 mmol/L). A meta-regression analysis showed that the hyponatremia-related risk of overall mortality was inversely correlated with serum [Na⁺]. This association was confirmed in a multiple regression model after adjusting for age, gender, and diabetes mellitus as an associated morbidity.</p><p>Conclusions</p><p>This meta-analysis shows for the first time that even a moderate serum [Na⁺] decrease is associated with an increased risk of mortality in commonly observed clinical conditions across large numbers of patients.</p></div

Studies included in meta-analysis.

<p>H: patients with hyponatremia; NH: patients without hyponatremia; DM: diabetes mellitus; NA: not available.</p

Relation between serum [Na⁺] cut-off definition and overall mortality risk.

<p>Relation between serum [Na⁺] cut-off definition and overall mortality risk.</p