Springer Science and Business Media LLC

There are unique challenges in the treatment and prevention of acute coronary syndromes (ACS) with antithrombotics in elderly patients: elderly patients usually require multiple drugs due to comorbidities, are highly susceptible to adverse drug reactions and drug–drug interactions, may have cognitive problems affecting compliance and complications, are especially exposed to the risk of falls and, most importantly, ageing is an independent risk factor for bleeding. Antithrombotic drugs, alone or in association, further and variously amplify age-related bleeding risk. Moreover, age-related changes in primary haemostasis may potentially affect the pharmacodynamics of some antiplatelet drugs. Thus, elderly subjects might be more or less sensitive to standard antiplatelet regimens depending on individual characteristics affecting antiplatelet drug response. Importantly, elderly patients are a rapidly growing population worldwide, have the highest incidence of ACS, but are poorly represented in clinical trials. As a consequence, evidence on antithrombotic drug benefits and risks is limited. Thus, in the real-world setting, older people are often denied antithrombotic drugs because of unjustified concerns, or might be over-treated and exposed to excessive bleeding risk. Personalized antithrombotic therapy in elderly patients is particularly critical, to minimize risks without affecting efficacy.

The efficacy of inhaled corticosteroids in the treatment of asthma has been firmly established in a variety of settings. The majority of asthma management plans now recommend the use of inhaled corticosteroids at an early stage. This means that most patients with asthma will be prescribed an inhaled corticosteroid at some point in time and many patients with asthma will use these drugs for several years. Inhaled corticosteroids are also used in the treatment of other conditions, particularly chronic obstructive pulmonary disease (COPD). Since inhaled corticosteroids are absorbed into the systemic circulation, they can have systemic adverse effects, such as suppression of the hypothalamic-pituitary-adrenal axis and increasing the risk of bruising. However, perhaps the greatest concern for patients is whether the regular use of inhaled corticosteroids has an adverse impact on the bone mineral density and increases the risk of fracture. There is now accumulating evidence from epidemiological studies that the use of inhaled corticosteroids is inversely related to bone mineral density in a dose-dependent fashion. However, data from two clinical trials of moderately high doses of inhaled corticosteroids in patients with COPD have produced conflicting results and while the larger study of triamcinolone found a significant impact of this drug on bone mineral density, a smaller study of budesonide found no effect. Epidemiological research into the relationship between inhaled corticosteroids and fracture is at an early stage. To date, only three studies in this area have been reported, all of which have used different approaches to try to minimise the impact of bias and confounding. There is a lack of consistency between the final estimates of the impact of inhaled corticosteroids on fracture risk. However, taken together these data suggest that the short to medium term use of inhaled corticosteroids is associated with a small adverse effect on bone. Doctors and patients need to be aware of this risk and balance it against the known beneficial effects of inhaled corticosteroids.

Context: Tolterodine is a bladder-selective antimuscarinic agent designed for the treatment of overactive bladder. Traditional antimuscarinic therapies are poorly tolerated due to a high incidence of anticholinergic adverse events and consequently few patients remain on long term therapy. Objective: To evaluate the long term efficacy and tolerability of tolterodine in patients with symptoms of overactive bladder. Design: Twelve-month open-label extension of 4 randomised, placebo-controlled, double-blind, multinational, multicentre trials of 4 weeks’ duration. Patients: 714 patients (aged 18 to 92 years) with symptoms of overactive bladder who completed the double-blind portion of the studies. Intervention: Tolterodine 2mg twice daily for up to 12 months. Main outcome measures: Micturition diary variables: number of micturitions per 24 hours, number of urge incontinence episodes per 24 hours, mean urine volume voided per micturition. Safety variables: adverse events, study discontinuation rate. Results: A total of 441 patients (62%) completed 12 months’ open-label treatment with tolterodine, which significantly reduced the number of micturitions per 24 hours [mean change −2.4, 95% confidence interval (CI) −2.7 to −2.2, median change −20%, p < 0.0001] and number of urge incontinence episodes per 24 hours (mean change −1.3, 95% CI −1.6 to −1.0, median change −74%, p < 0.0001), while the mean volume voided per micturition was significantly increased (+33ml, 95% CI +28 to +38, median change +18%; p < 0.0001). 41% of patients reported dry mouth (27% mild, 10% moderate, 3% severe). Dosage reduction to 1mg twice daily was required in 23% of patients. 15% of patients withdrew from the study due to adverse events, with 5% having associated dry mouth. Conclusions: The high percentage of patients completing 12 months’ treatment indicates that tolterodine is an effective and well tolerated agent for long term treatment of overactive bladder.

The US Food and Drug Administration’s decisions about drug approval—though guided by science, as well as relevant statutes, regulations, and guidance documents—reflect normative judgments about how the agency should exercise its discretion. This is particularly true in the context of the “accelerated approval” pathway, where the agency must balance speeding to market drugs for patients with unmet needs before they have been proven to work and ensuring confidence about the benefits and risks of those drugs. A key challenge in evaluating normative judgments such as these is that reasonable people can disagree, rendering it difficult to proclaim with certainty that a particular decision is right or wrong. Therefore, we propose that it is preferable to ask whether a decision is reasonable. A decision is reasonable when it transparently, comprehensively, and fairly balances the interests of affected parties, within the parameters of the decision maker’s legal authority. If a decision achieves these three qualities, it can be viewed as legitimate and worthy of trust and confidence, regardless of whether one agrees with the particular outcome. We recommend that the Food and Drug Administration adopt procedural protections to promote reasonableness in four domains affecting accelerated approval decisions: pathway gatekeeping, endpoint selection, stakeholder engagement, and deliberation. This should aid the agency in minimizing controversies, such as that surrounding the 2021 approval of aducanumab (Aduhelm; Biogen).

Melatonin is a hormone that regulates circadian rhythm, and its levels decline with age. As melatonin levels decrease, older adults are prone to develop disorders related to an altered circadian rhythm. The effective dose of melatonin supplementation in these disorders remains unclear. Our objective was to define the optimal dosage of exogenous melatonin administration in disorders related to altered melatonin levels in older adults aged 55 years and above by determining the dose-response effect of exogenous administered melatonin on endogenous levels. We conducted a systematic review through PubMed/MEDLINE and Embase, both from 1980 until November 2013. Included articles studied the effect of exogenous melatonin administration on endogenous melatonin levels in either serum, urine, or saliva in humans aged 55 years and above. We included 16 articles, nine of which were randomized controlled trials (RCTs). The mean age varied from 55.3 to 77.6 years. Melatonin dosage varied from 0.1 mg to 50 mg/kg and was administered orally in all studies. Pre- and post-intervention levels revealed a significant elevation of the post-intervention melatonin levels in a dose-dependent fashion. The maximum concentrations measured in serum and urine were all elevated compared with placebo, and a higher elevation in older adults than in younger adults was demonstrated. Even though there were no differences between times to reach maximum concentration in serum and urine, melatonin levels with higher doses were maintained longer above a certain threshold than were lower doses. In older adults, we advise the use of the lowest possible dose of immediate-release formulation melatonin to best mimic the normal physiological circadian rhythm of melatonin and to avoid prolonged, supra-physiological blood levels.