A year in review: new drugs for older adults in 2011

BackgroundNew drugs approved by the Food and Drug Administration (FDA) may offer tremendous clinical advances by providing health care providers with new treatment strategies. However, additional care must be taken for safe and effective use of these new agents by older adults.ObjectiveOur objective was to identify FDA-approved medications in 2011 most likely to be prescribed to older adults, and to describe medication characteristics that may require special attention in this population.MethodsThe FDA Web site was reviewed for new drug approvals from January through December 2011. Approved labeling for each drug was obtained from the manufacturer's Web site and PubMed was searched for primary literature published between 1967 and 2012.ResultsRivaroxaban, an oral factor Xa inhibitor, is approved for once-daily use in treatment of nonvalvular atrial fibrillation and deep vein thrombosis prophylaxis after replacement of a hip or knee. Drug interactions and renal function must be considered when prescribing this drug to older adults. Fidaxomicin is an oral anti-infective approved for the treatment of Clostridium difficile-associated diarrhea. It has minimal oral absorption or side effects, no relevant drug interactions, but a very high cost. It is a treatment option after failure of oral metronidazole and oral vancomycin. Roflumilast is a selective inhibitor of phosphodiesterase 4 and is approved to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD and a history of exacerbations. It is recommended as a second or alternative choice combined with a long-acting bronchodilator in patients at high risk for hospitalization. Indacaterol is an inhaled long-acting β-agonist approved for COPD maintenance. It is administered once daily, which may improve adherence in older adults compared with currently available twice-daily agents.ConclusionsFour new drugs approved in 2011 applicable to the geriatric population are presented. Clinicians must consider the available evidence, cost, drug–drug interactions, renal function, pharmacokinetic/pharmacodynamic differences, and patient preferences when considering prescribing these agents to older adults.     

Proton Pump Inhibitors: Review of Emerging Concerns

First introduced in 1989, proton pump inhibitors (PPIs) are among the most widely utilized medications worldwide, both in the ambulatory and inpatient clinical settings. The PPIs are currently approved by the US Food and Drug Administration for the management of a variety of gastrointestinal disorders including symptomatic peptic ulcer disease, gastroesophageal reflux disease, and nonulcer dyspepsia as well as for prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. PPIs inhibit gastric acid secretion, and the most commonly associated adverse effects include abdominal pain, diarrhea, and headache. Although PPIs have had an encouraging safety profile, recent studies regarding the long-term use of PPI medications have noted potential adverse effects, including risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B₁₂ deficiency, chronic kidney disease, and dementia. These emerging data have led to subsequent investigations to assess these potential risks in patients receiving long-term PPI therapy. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. Hence, when clinically indicated, PPIs can be prescribed at the lowest effective dose for symptom control.     

Serious Adverse Drug Reactions in Older Adults Notified to Pharmacovigilance

PurposeTo report the serious adverse drug reactions (ADRs) in older adults notified to pharmacovigilance, to identify the incriminated drugs and to search for risk factors of occurrence.MethodsA retrospective study including 106 serious adverse drug reactions notified to pharmacovigilance in patients aged of 65 years and more, over a period of 16 years. Imputation was established according to the French method and seriousness according to the World Health Organisation (WHO) criteria.ResultsAdverse drug reactions were essentially systemic. Incriminated drugs were mainly antibiotics, allopurinol and cardio-vascular drugs. Gender, age and number of administered drugs did not seem to be risk factors of serious ADRs occurrence. Among older adults, 4% died further to a serious ADRs.ConclusionSystemic notification to pharma covigilance will allow a better analysis of risk factors of serious ADRs occurrence and to insure safety and health to the older adults.     

The Food and Drug Administration Risk Evaluation and Mitigation Strategy

ABSTRACT

The Food and Drug Administration Amendments Act of 2007 extended the agency's regulatory authority over drug products that have been shown to place patients at risk. This Act authorizes the FDA to require pharmaceutical manufacturers and distributors to ensure that the safety of their products continue to outweigh the risks. This article discusses in more detail the proposed elements of an acceptable Risk Evaluation and Mitigation Strategy (REMS) for any drug product, including extended-release opioid analgesics.     

Statins for the primary prevention of cardiovascular events in older adults: a review of the evidence

Background:Although statins have been demonstrated to be beneficial for secondary prevention in the elderly, their use for primary prevention has not been well described.Objective:In this review, we summarize data regarding the efficacy, safety, and current recommendations for statins for the primary prevention of cardiovascular events in older adults.Methods:This review is based on a computerized literature search of the PubMed database for articles published in the English language from January 1980 to June 2006. Key words searched individually and cross-referenced included: statins, HMG-CoA reductase inhibitors, cholesterol, elderly, aged, cardiovascular disease, primary prevention, risk stratification, and C-reactive protein. This search produced 445 citations; reference lists revealed an additional 12 citations, all of which were screened for relevance to the topic.Results:The existing evidence suggests, but does not confirm, benefit from the use of statins for primary prevention in the elderly subgroup (ie, those aged ≥65 years). Of the 6 published trials of statins for primary prevention, only 3 included subjects aged >75 years, and subgroup results in older adults are unavailable. Current guidelines recommend statins for individuals based on their assessed cardiovascular risk.Conclusions:Extension of treatment guidelines should consider an individual's global risk of coronary heart disease. However, due to the prevalence of subclinical disease in older adults, risk may be higher or otherwise differ with age. In addition, tolerance for and barriers to adherence with long-term medical therapy are important treatment considerations in older adults. Prospective, randomized controlled trials that better define the tolerability, safety, and efficacy of statin therapy in older adults with elevated cholesterol levels and intermediate cardiovascular risk are needed.     

Characterization and risk factors for recurrence of Clostridioides (Clostridium) difficile infection in Japan: A nationwide real-world analysis using a large hospital-based administrative dataset

ObjectiveRecurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database.MethodsC. difficile infection (CDI) episodes, occurring July 2014–June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model.ResultsOf 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75–84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval [1.15, 1.41] and 1.45 [1.30, 1.61], respectively). Use of systemic antibiotics (3.16 [2.90, 3.44]), probiotics (2.53 [2.32, 2.77]), chemotherapy (1.28 [1.08, 1.53]), or proton pump inhibitors (PPIs) (1.17 [1.07, 1.28]), and prior CDI history (1.22 [1.03, 1.43]) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 [0.76, 0.91]).ConclusionThis large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment.Clinical trial registration number: N/A.     

Effectiveness and safety of Dabigatran 110 mg versus 150 mg for Stroke Prevention in Patients with Atrial Fibrillation at High Bleeding Risk

PurposeThe effectiveness and tolerability of a reduced dose (110 mg) of dabigatran versus the standard dose (150 mg) were evaluated in subgroups of patients with atrial fibrillation (AF) at high bleeding risk.MethodsEligible patients were adults with AF and a creatinine clearance rate ≥30 mL/min who were initiated on treatment with dabigatran (index) between 2016 and 2018. High–bleeding-risk subgroups were identified: (1) age ≥80 years; (2) moderate renal impairment (creatinine clearance rate 30–<50 mL/min); and (3) recent bleeding or a HAS-BLED score of ≥3. Fine-Gray subdistribution hazard regression models with inverse probability of treatment weights were used to investigate associations between dabigatran dose and three outcomes: stroke or systemic embolism, major bleeding requiring hospitalization, and all-cause mortality.FindingsAmong 7858 patients with AF and a high bleeding risk (age ≥80 years, 3472; moderate renal impairment, 1574; recent bleeding or HAS-BLED score ≥3, 2812), 32.3% received reduced-dose dabigatran. Compared with the standard dose, use of the reduced dose of dabigatran was not associated with an increased risk for stroke or systemic embolism but was associated with a lower risk for major bleeding (HR = 0.65; 95% CI, 0.44–0.95) and all-cause mortality (HR = 0.78; 95% CI, 0.65–0.92) in patients aged ≥80 years. The use of reduced-dose dabigatran was associated with a lower risk for major bleeding (HR = 0.54; 95% CI, 0.30–0.95) and all-cause mortality among patients with moderate renal impairment (HR = 0.53; 95% CI, 0.40–0.71).ImplicationsLower risks for bleed and mortality associated with reduced- versus standard-dose dabigatran in patients with AF and a high bleeding risk suggest a better dosing strategy.     

Disparity between perceived and physiological risks of falling among older patients in an acute care hospital

BackgroundFalls are the most frequent adverse events among hospitalised older adults. Previous studies highlighted that older adults might not understand the risk factors associated with falls and may have an altered perception of their actual risk.AimTo describe differences between perceived and actual physiological risk of falling among older adults and to explore factors associated with the differences.Methods: A prospective cohort study was done. Older adults (age 65 years and above) were interviewed one-to-one at bedside. Morse Fall Scale (MFS) and other risk factors for falls were used to identify the patients’ physiological fall risks. Patients’ perceived risk of falls were assessed using the Falls Efficacy Scale-International (FES-I).ResultsThree hundred patients were recruited. Patients’ mean age was 75.3 (SD = ± 6.2). Majority were males (51.7%), lived with others (91.7%), and had received primary school education (35.3%). Based on the MFS, most patients had moderate fall risk (59.7%). Using the FES-I, more than half the patients (59%) interviewed had high concerns about falling. About one-third of the patients’ (31.3%) perceived risk matched with their physiological fall risk (Risk-Aware). Half of the patients’ perceived risks was higher than their physiological fall risk (50.7%) (Risk-Anxious), while the remaining patients’ perceived risks was reported to be lower than their physiological fall risk (18%) (Risk-Taker).ConclusionOlder patients are poor at recognizing their fall risks. Both patients’ perceived and actual fall risks should be evaluated in the inpatient setting in order to inform individualized fall prevention education and strategies.     

Dabigatran in Clinical Practice

BackgroundStroke and systemic thromboembolism remain critical causes of mortality and morbidity in patients with paroxysmal or persistent atrial fibrillation. Dabigatran etexilate is a novel oral direct thrombin inhibitor, which provides stroke risk reduction for patients with nonvalvular atrial fibrillation. Randomized clinical data demonstrate dabigatran to be an alternative oral anticoagulant with an improved efficacy profile compared with oral warfarin dose adjusted to an INR (international normalized ratio) target of 2.0 to 3.0.ObjectivesOur aim was to review the pharmacology, mechanism of action, drug metabolism, and clinical trial data supporting dabigatran use.MethodsWe reviewed all the major published clinical studies of dabigatran and analyzed data regarding practical applications in selected clinical scenarios.ResultsThis review provides recommendations for clinicians regarding dosing during invasive surgical procedures, transitioning off alternative anticoagulants, and a discussion of storage and handling of the drug.ConclusionsOur effort should facilitate the safe and effective use of dabigatran in atrial fibrillation.     

Adverse Effects of Analgesics Commonly Used by Older Adults With Osteoarthritis: Focus on Non-Opioid and Opioid Analgesics

BackgroundOsteoarthritis (OA) is the most common cause of disability in older adults, and although analgesic use can be helpful, it can also result in adverse drug events.ObjectiveTo review the recent literature to describe potential adverse drug events associated with analgesics commonly used by older adults with OA.MethodsTo identify articles for this review, a systematic search of the English-language literature from January 2001 to June 2012 was conducted using PubMed, MEDLINE, EBSCO, and the Cochrane Database of Systematic Reviews for publications related to the medical management of OA. Search terms used were “analgesics,” “acetaminophen,” “nonsteroidal anti-inflammatory drugs” (NSAIDs), “opioids,” “pharmacokinetics,” “pharmacodynamics,” and “adverse drug events.” The search was restricted to those articles that concerned humans aged ≥65 years. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. From these, the authors identified those studies that examined analgesic use in older adults.ResultsThere are limited data to suggest that non-frail elders are more likely than their younger counterparts to develop acetaminophen-induced hepatotoxicity. However, decreased hepatic phase II metabolism in frail elders may result in increased risk of hepatotoxicity. It is now well established that older adults are at higher risk of NSAID-induced gastrointestinal toxicity and renal insufficiency. Insofar as opioids, the data that suggest an increased risk of falls, fractures, or delirium need to be tempered by the potential risk of inadequately treating severe chronic OA-related pain.ConclusionsAcetaminophen is the mainstay frontline analgesic for treating OA-related pain in older adults. NSAIDs should be limited to short-term use only, and for moderate to severe OA-related pain, opioids may be preferable in individuals without substance abuse or dependence issues.     

Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring

Context: Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications – however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function. Case details: Two patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10?×?150?mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100?×?110?mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels. Conclusion: There is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.     

Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials

Purpose

Stress ulcer prophylaxis (SUP) is commonly prescribed in the intensive care unit. However, data from systematic reviews and conventional meta-analyses are limited by imprecision and restricted to direct comparisons. We conducted a network meta-analysis of randomized clinical trials (RCTs) to examine the safety and efficacy of drugs available for SUP in critically ill patients.

Methods

We searched MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials through April 2017 for randomized controlled trials that examined the efficacy and safety of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and sucralfate for SUP in critically ill patients. No date or language restrictions were applied. Data on study characteristics, methods, outcomes, and risk of bias were abstracted by two reviewers.

Results

Of 96 potentially eligible studies, we included 57 trials enrolling 7293 patients. The results showed that PPIs are probably more effective for preventing clinically important gastrointestinal bleeding (CIB) than H2RAs [odds ratio (OR) 0.38; 95% confidence interval (95% CI) 0.20, 0.73], sucralfate (OR 0.30; 95% CI 0.13, 0.69), and placebo (OR 0.24; 95% CI 0.10, 0.60) (all moderate quality evidence). There were no convincing differences among H2RA, sucralfate, and placebo. PPIs probably increase the risk of developing pneumonia compared with H2RAs (OR 1.27; 95% CI 0.96, 1.68), sucralfate (OR 1.65; 95% CI 1.20, 2.27), and placebo (OR 1.52; 95% CI 0.95, 2.42) (all moderate quality). Mortality is probably similar across interventions (moderate quality). Estimates of baseline risks of bleeding varied significantly across studies, and only one study reported on Clostridium difficile infection. Definitions of pneumonia varied considerably. Most studies on sucralfate predate pneumonia prevention strategies.

Conclusions

Our results provide moderate quality evidence that PPIs are the most effective agents in preventing CIB, but they may increase the risk of pneumonia. The balance of benefits and harms leaves the routine use of SUP open to question.

     

Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea?

Proton pump inhibitors (PPIs) have been identified as a risk factor for Clostridium difficile-associated diarrhea (CDAD), though the mechanism is unclear because gastric acid does not kill C. difficile spores. We hypothesized that the vegetative form of C. difficile, which is killed by acid, could contribute to disease pathogenesis if it survives in room air and in gastric contents with elevated pH. We compared the numbers of C. difficile spores and vegetative cells in stools of patients prior to and during the treatment of CDAD. We assessed the survival of vegetative cells on moist or dry surfaces in room air versus anaerobic conditions and in human gastric contents, in pH-adjusted gastric contents, and in gastric contents from individuals receiving PPI therapy. Stool samples obtained from patients prior to the initiation of antibiotic treatment for C. difficile contained ~10-fold more vegetative cells than spores. On dry surfaces, vegetative C. difficile cells died rapidly, whereas they remained viable for up to 6 h on moist surfaces in room air. Vegetative C. difficile cells had only marginal survival in gastric contents at low pH; adjustment to a pH of >5 resulted in survival similar to that in the phosphate-buffered saline control. The survival of vegetative C. difficile in gastric contents obtained from patients receiving PPIs was also increased at a pH of >5. The ability of the vegetative form of C. difficile to survive on moist surfaces and in gastric contents with an elevated pH suggests a potential mechanism by which PPI therapy could increase the risk of acquiring C. difficile.     

Isolement social et solitude : les nouveaux géants gériatriques: Approche à l’intention des soins primaires

ObjectiveTo review the problems of social isolation, loneliness, and social vulnerability in older adults and the associated risks, and to help primary care providers identify patients at risk and recommend effective interventions.Sources of informationPubMed and PsycINFO searches were conducted using the terms aged, social isolation, loneliness, screening, and interventions and associated key words for relevant English-language articles. References of identified articles were also hand searched. A separate search of the gray literature using Google was conducted to find policy documents and knowledge translation materials from relevant organizations. The search covered relevant articles from the 10 years before June 2019.Main messageSocial isolation, loneliness, and social vulnerability are very common in older adults and are associated with considerable morbidity and mortality, comparable to established risk factors such as smoking, alcohol consumption, obesity, and frailty. Numerous interventions addressing loneliness and social isolation have been studied: social facilitation (including technology), exercise, psychological therapies, health and social services, animal therapy, befriending, and leisure and skill development. However, current evidence of effectiveness is limited. A patient-centred approach is essential to the selection of interventions. The needs of underserviced and marginalized populations, including new immigrants, older adults identifying as LGBTQ+ (lesbian, gay, bisexual, transgender, queer or questioning, and related communities), Indigenous seniors, and seniors living in poverty, as well as the needs of long-term care residents and older caregivers, require further evaluation.ConclusionSocial isolation, loneliness, and social vulnerability are common problems in older adults and have important health consequences. Family physicians are uniquely positioned to identify lonely and socially isolated older adults and to initiate services.     

Risks of combined alcohol/medication use in older adults

Background:Many older adults (ie, those aged ≥65 years) drink alcohol and use medications that may be harmful when consumed together.Objective:This article reviews the literature on alcohol and medication interactions, with a focus on older adults.Methods:Relevant articles were identified through a search of MEDLINE and International Pharmaceutical Abstracts (1966–August 2006) for English-language articles. The following medical subject headings and key words were used: alcohol medication interactions, diseases worsened by alcohol use, and alcohol metabolism, absorption, and distribution. Additional articles were identified by a manual search of the reference lists of the identified articles, review articles, textbooks, and personal reference sources.Results:Many older adults drink alcohol and take medications that may interact negatively with alcohol. Some of these interactions are due to age-related changes in the absorption, distribution, and metabolism of alcohol and medications. Others are due to disulfiram-like reactions observed with some medications, exacerbation of therapeutic effects and adverse effects of medications when combined with alcohol, and alcohol's interference with the effectiveness of some medications.Conclusions:Older adults who drink alcohol and who take medications are at risk for a variety of adverse consequences depending on the amount of alcohol and the type of medications consumed. It is important for clinicians to know how much alcohol their older patients are drinking to be able to effectively assess their risks and to counsel them about the safe use of alcohol and medications. Similarly, it is important for older adults to understand the potential risks of their combined alcohol and medication use to avoid the myriad of problems possible with unsafe use of these substances.     

Woman with hemorrhagic spots on her abdomen

Abstract

Lipodissolve is a product that is composed of phosphatidylcholine and deoxycholate mixture, and other adjuvant. Lipodissolve injection seems to be performed in many countries for local fat reduction without any legal and scientific evidences of its safety and efficacy despite the US FDA warning.1 Herein, we report a case with agitation and metabolic acidosis following lipodissolve injection.     

Is ondansetron safe for use during pregnancy?

Question While I usually prescribe doxylamine-pyridoxine for morning sickness, some of my patients with severe nausea and vomiting of pregnancy (NVP) receive ondansetron in hospital. I have read some new precautions recommended by the US Food and Drug Administration (FDA). Is ondansetron safe to use during pregnancy?Answer During the past decade ondansetron has been increasingly used in the United States for NVP, owing to the lack of an FDA-approved drug for this condition. While fetal safety data for doxylamine-pyridoxine are based on more than a quarter of a million pregnancies, the fetal safety data for ondansetron are based on fewer than 200 births. Moreover, a recent case-control study suggested there was an increased risk of cleft palate associated with ondansetron. Recently, the FDA issued a warning about potentially serious QT prolongation and torsade de pointes associated with ondansetron use; the warning included a list of precautions and tests that must be followed. The drug is not labeled for use in NVP in either the United States or Canada. Based on the data available today, ondansetron use cannot be assumed to be safe during pregnancy.     

Idarucizumab for dabigatran overdose

Context: An overdose of oral anticoagulants represents a challenging scenario for emergency physicians. Dabigatran, an oral direct thrombin inhibitor, is increasingly used in place of warfarin. The lack of an antidote is a concern in patients who overdose on dabigatran, even though the drug can be eliminated with hemodialysis. Idarucizumab is an antibody fragment that binds dabigatran with high affinity. It reverses the anticoagulant effect of dabigatran within minutes and is approved for the reversal of dabigatran during emergency situations.

Case details: We describe the use of idarucizumab in the management of a 68-year-old woman who was taking dabigatran 150?mg twice daily and ingested 125 capsules. Despite gastric lavage and administration of activated charcoal within two hours of drug intake, the activated partial thromboplastin time (aPTT) and prothrombin time (PT) remained prolonged. The administration of 5?g of intravenous idarucizumab promptly and completely reversed the anticoagulant activity of dabigatran as assessed by routine and specific coagulation assays (aPTT from to 75 to 26?s, PT from 26 to 11?s and diluted thrombin time from 92 to 27?s). The initially planned emergency hemodialysis was canceled.

Discussion: This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses.