Azacytidine for acute myeloid leukemia in elderly or frail patients: A phase II trial (SAKK 30/07)

Abstract This phase II trial treated elderly or frail AML patients with single agent subcutaneous azacytidine at 100 mg/m(2), on 5 of 28 days for up to 6 cycles. Treatment was stopped for lack of response, or continued to progression in responders. Primary endpoint was response within 6 months. A response rate >34% was considered a positive trial outcome. From 9/2008-4/2010, 45 patients from 10 centres (median age 74 (55-86) years) were accrued. Patients received 4 (1-21) cycles. Best response was CR/CRi in 8 (18%; 95% CI: 8%-32%.), 0 (0%) PR, 7 (16%) hematologic improvement, 17 (38%) stable disease. Three nonresponding patients stopped treatment after 6 cycles, 31 patients had stopped early and 11 patients continued treatment for 8-21 cycles. Adverse events (grade >III) were infections (13), febrile neutropenia (14), thrombocytopenia (7), dyspnea (6), bleeding (5) and anemia (4 patients). Median overall survival was 6 months. Peripheral blood blast counts, grouped at 30% had a borderline significant association with response (p = 0.07). This modified azacytidine schedule is feasible for elderly or frail AML patients in an outpatient setting with moderate, mainly hematologic, toxicity and response in a proportion of patients, although the primary objective was not reached.

Etomidate for critically ill patients. Con: do you really want to weaken the frail?

Etomidate is an imidazole-derived hypnotic agent preferentially used for rapid sequence induction of anaesthesia because of its favourable haemodynamic profile. However, 11β-hydroxylase inhibition causes adrenal insufficiency with potentially fatal consequences in specific populations. We review the arguments against the liberal administration of etomidate in critically ill, and especially septic, patients. This review considered only high-quality and prospective studies with a low risk of bias. Three major effects have been observed with the clinical use of a single dose of etomidate. First, independent of the clinical setting, etomidate causes adrenal dysfunction via 11β-hydroxylase inhibition ranging from 12 to 48 h, making the drug unsuitable for use in elective interventions. Second, in a systematic review with meta-analyses, including 3715 septic patients, the relative risk of death with etomidate was 1.22 (95% confidence interval 1.11 to 1.35). Based on this statistically significant and clinically relevant increase in mortality, a single dose of etomidate has to be avoided in patients with septic shock. Third, in small randomised controlled trials, a single dose of etomidate in trauma patients was associated with an increased incidence of pneumonia (56.7 vs. 25.9% in controls), prolonged intensive care stay (6.3 vs. 1.5 days) and prolonged hospital stay (11.6 vs. 6.4 days). Based on these randomised controlled trials, the use of etomidate should be avoided in unstable trauma patients. Midazolam and ketamine are two valid alternatives with similar intubation and haemodynamic conditions as etomidate but without its adverse effects. Therefore, for safety reasons, etomidate should be avoided in the critical conditions of sepsis and trauma

Chapter VI: Follow-up after revascularisation

Structured follow-up after revascularisation for chronic critical limb ischaemia (CLI) aims at sustained treatment success and continued best patient care. Thereby, efforts need to address three fundamental domains: (A) best medical therapy, both to protect the arterial reconstruction locally and to reduce atherosclerotic burden systemically; (B) surveillance of the arterial reconstruction; and (C) timely initiation of repeat interventions. As most CLI patients are elderly and frail, sustained resolution of CLI and preserved ambulatory capacity may decide over independent living and overall prognosis. Despite this importance, previous guidelines have largely ignored follow-up after CLI; arguably because of a striking lack of evidence and because of a widespread assumption that, in the context of CLI, efficacy of initial revascularisation will determine prognosis during the short remaining life expectancy. This chapter of the current CLI guidelines aims to challenge this disposition and to recommend evidentially best clinical practice by critically appraising available evidence in all of the above domains, including antiplatelet and antithrombotic therapy, clinical surveillance, use of duplex ultrasound, and indications for and preferred type of repeat interventions for failing and failed reconstructions. However, as corresponding studies are rarely performed among CLI patients specifically, evidence has to be consulted that derives from expanded patient populations. Therefore, most recommendations are based on extrapolations or subgroup analyses, which leads to an almost systematic degradation of their strength. Endovascular reconstruction and surgical bypass are considered separately, as are specific contexts such as diabetes or renal failure; and critical issues are highlighted throughout to inform future studies.

Chapter III: Management of cardiovascular risk factors and medical therapy

Critical limb ischaemia (CLI) is a particularly severe manifestation of lower limb atherosclerosis posing a major threat to both limb and life of affected patients. Besides arterial revascularisation, risk-factor modification and administration of antiplatelet therapy is a major goal in the treatment of CLI patients. Key elements of cardiovascular risk management are smoking cessation and treatment of hyperlipidaemia with dietary modification or statins. Moreover, arterial hypertension and diabetes mellitus should be adequately treated. In CLI patients not suitable for arterial revascularisation or subsequent to unsuccessful revascularisation, parenteral prostanoids may be considered. CLI patients undergoing surgical revascularisation should be treated with beta blockers. At present, neither gene nor stem-cell therapy can be recommended outside clinical trials. Of note, walking exercise is contraindicated in CLI patients due to the risk of worsening pre-existing or causing new ischaemic wounds. CLI patients are oftentimes medically frail and exhibit significant comorbidities. Co-existing coronary heart and carotid as well as renal artery disease should be managed according to current guidelines. Considering the above-mentioned treatment goals, interdisciplinary treatment approaches for CLI patients are warranted. Aim of the present manuscript is to discuss currently existing evidence for both the management of cardiovascular risk factors and treatment of co-existing disease and to deduct specific treatment recommendations.

[Gerodontology consultation in geriatric facilities: general health status (I)]

Dental undertreatment is often seen in the older population. This is particularly true for the elderly living in nursing homes and geriatric hospitals. The progression of chronic diseases results in loss of their independence. They rely on daily support and care due to physical or mental impairment. The visit of a dentist in private praxis becomes difficult or impossible and is a logistic problem. These elderly patients are often not aware of oral and dental problems or these are not addressed. The geriatric hospital Bern, Ziegler, has integrated dental care in the concept of physical rehabilitation of geriatric patients. A total of 139 patients received dental treatment in the years 2005/2006. Their mean age was 83 years, but the segment with > 85 years of age amounted to 46%. The general health examinations reveald multiple and complex disorders. The ASA classification (American Society of Anesthesiologists, Physical Status Classification System) was applied and resulted in 15% = P2 (mild systemic disease, no functional limitation), 47% = P3 (severe systemic disease, definite functional limitations) and 38% = P4 (severe systemic disease, constant threat to life). Eighty-seven of the patients exhibited 3 or more chronic diseases with a prevalence of cardiovascular diseases, musculoskelettal disorders and dementia. Overall the differences between men and women were small, but broncho-pulmonary dieseases were significantly more frequent in women, while men were more often diagnosed with dementia and depression. Verbal communication was limited or not possible with 60% of the patients due to cognitive impairment or aphasia after a stroke. Although the objective treatment need is high, providing dentistry for frail and geriatric patients is characterized by risks due to poor general health conditions, difficulties in communication, limitations in feasibility and lack of adequate aftercare. In order to prevent the problem of undertreatment, elderly independently living people should undergo dental treatment regularly and in time. Training of nurses and doctors of geriatric hospitals in oral hygiene should improve the awareness. A multidisciplinary assessment of geriatric patients should include the oral and dental aspect if they enter the hospital.

Frailty and risk for heart failure in older adults: the health, aging, and body composition study

OBJECTIVE The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. BACKGROUND Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. METHODS We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. RESULTS Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). CONCLUSIONS Frailty is independently associated with risk of HF in older adults.

Intermittent hemodialysis treatment in cefepime-induced neurotoxicity: Case report, pharmacokinetic modeling, and review of the literature

Cefepime is a broad-spectrum cephalosporin indicated for in-hospital treatment of severe infections. Acute neurotoxicity, an increasingly recognized adverse effect of this drug in an overdose, predominantly affects patients with reduced renal function. Although dialytic approaches have been advocated to treat this condition, their role in this indication remains unclear. We report the case of an 88-year-old female patient with impaired renal function who developed life-threatening neurologic symptoms during cefepime therapy. She was treated with two intermittent 3-hour high-flux, high-efficiency hemodialysis sessions. Serial pre-, post-, and peridialytic (pre- and postfilter) serum cefepime concentrations were measured. Pharmacokinetic modeling showed that this dialytic strategy allowed for serum cefepime concentrations to return to the estimated nontoxic range 15 hours earlier than would have been the case without an intervention. The patient made a full clinical recovery over the next 48 hours. We conclude that at least 1 session of intermittent hemodialysis may shorten the time to return to the nontoxic range in severe clinically patent intoxication. It should be considered early in its clinical course pending chemical confirmation, even in frail elderly patients. Careful dosage adjustment and a high index of suspicion are essential in this population.

European undergraduate curriculum in geriatric medicine developed using an international modified Delphi technique.

INTRODUCTION the rise in the number of older, frail adults necessitates that future doctors are adequately trained in the skills of geriatric medicine. Few countries have dedicated curricula in geriatric medicine at the undergraduate level. The aim of this project was to develop a consensus among geriatricians on a curriculum with the minimal requirements that a medical student should achieve by the end of medical school. METHODS a modified Delphi process was used. First, educational experts and geriatricians proposed a set of learning objectives based on a literature review. Second, three Delphi rounds involving a panel with 49 experts representing 29 countries affiliated to the European Union of Medical Specialists (UEMS) was used to gain consensus for a final curriculum. RESULTS the number of disagreements following Delphi Rounds 1 and 2 were 81 and 53, respectively. Complete agreement was reached following the third round. The final curriculum consisted of detailed objectives grouped under 10 overarching learning outcomes. DISCUSSION a consensus on the minimum requirements of geriatric learning objectives for medical students has been agreed by European geriatricians. Major efforts will be needed to implement these requirements, given the large variation in the quality of geriatric teaching in medical schools. This curriculum is a first step to help improve teaching of geriatrics in medical schools, and will also serve as a basis for advancing postgraduate training in geriatrics across Europe.

Awareness of Stroke Risk after TIA in Swiss General Practitioners and Hospital Physicians.

BACKGROUND Transient ischemic attacks (TIA) are stroke warning signs and emergency situations, and, if immediately investigated, doctors can intervene to prevent strokes. Nevertheless, many patients delay going to the doctor, and doctors might delay urgently needed investigations and preventative treatments. We set out to determine how much general practitioners (GPs) and hospital physicians (HPs) knew about stroke risk after TIA, and to measure their referral rates. METHODS We used a structured questionnaire to ask GPs and HPs in the catchment area of the University Hospital of Bern to estimate a patient's risk of stroke after TIA. We also assessed their referral behavior. We then statistically analysed their reasons for deciding not to immediately refer patients. RESULTS Of the 1545 physicians, 40% (614) returned the survey. Of these, 75% (457) overestimated stroke risk within 24 hours, and 40% (245) overestimated risk within 3 months after TIA. Only 9% (53) underestimated stroke risk within 24 hours and 26% (158) underestimated risk within 3 months; 78% (473) of physicians overestimated the amount that carotid endarterectomy reduces stroke risk; 93% (543) would rigorously investigate the cause of a TIA, but only 38% (229) would refer TIA patients for urgent investigations "very often". Physicians most commonly gave these reasons for not making emergency referrals: patient's advanced age; patient's preference; patient was multimorbid; and, patient needed long-term care. CONCLUSIONS Although physicians overestimate stroke risk after TIA, their rate of emergency referral is modest, mainly because they tend not to refer multimorbid and elderly patients at the appropriate rate. Since old and frail patients benefit from urgent investigations and treatment after TIA as much as younger patients, future educational campaigns should focus on the importance of emergency evaluations for all TIA patients.

The Importance of Patency in Patients with Critical Limb Ischemia Undergoing Endovascular Revascularization for Infrapopliteal Arterial Disease.

Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease (PAD) and frequently occurs in medically frail patients. CLI patients frequently exhibit multi-segmental PAD commonly including the tibial arterial segment. Endovascular therapy has been established as first-line revascularization strategy for most CLI patients. Restenosis was reported to occur in up to more than two-thirds of CLI patients undergoing angioplasty of complex tibial arterial obstructions. Nevertheless, favorable clinical outcomes were observed for infrapopliteal angioplasty when compared with bypass surgery, despite higher patency rates for the latter. Based on these observations, infrapopliteal patency was considered to be only of secondary importance upon clinical outcomes in CLI patients. In contrast to these earlier observations, however, recent findings from two randomized clinical trials indicate that infrapopliteal patency does impact on clinical outcomes in CLI patients. The purpose of the present manuscript is to provide a critical reappraisal of the present literature on the clinical importance of tibial arterial patency in CLI patients undergoing endovascular revascularization and to discuss utility and limitations of currently available anti-restenosis technologies.

Subclinical Thyroid Dysfunction and Frailty Among Older Men

CONTEXT Both subclinical thyroid dysfunction and frailty are common among older individuals, but data on the relationship between these 2 conditions are conflicting. OBJECTIVE The purpose of this study was to assess the cross-sectional and prospective associations between subclinical thyroid dysfunction and frailty and the 5 frailty subdomains (sarcopenia, weakness, slowness, exhaustion, and low activity). SETTING AND DESIGN The Osteoporotic Fractures in Men Study is a prospective cohort study. PARTICIPANTS Men older than 65 years (n = 1455) were classified into 3 groups of thyroid status: subclinical hyperthyroidism (n = 26, 1.8%), subclinical hypothyroidism (n = 102, 7.0%), and euthyroidism (n = 1327, 91.2%). MAIN OUTCOME MEASURES Frailty was defined using a slightly modified Cardiovascular Health Study Index: men with 3 or more criteria were considered frail, men with 1 to 2 criteria were considered intermediately frail, and men with no criteria were considered robust. We assessed the cross-sectional relationship between baseline thyroid function and the 3 categories of frailty status (robust/intermediate/frail) as well as the prospective association between baseline thyroid function and subsequent frailty status and mortality after a 5-year follow-up. RESULTS At baseline, compared with euthyroid participants, men with subclinical hyperthyroidism had an increased likelihood of greater frailty status (adjusted odds ratio, 2.48; 95% confidence interval, 1.15-5.34), particularly among men aged <74 years at baseline (odds ratio for frailty, 3.63; 95% confidence interval, 1.21-10.88). After 5 years of follow-up, baseline subclinical hypothyroidism and hyperthyroidism were not consistently associated with overall frailty status or frailty components. CONCLUSION Among community-dwelling older men, subclinical hyperthyroidism, but not subclinical hypothyroidism, is associated with increased odds of prevalent but not incident frailty.

Antithrombotic therapy in TAVI patients: changing concepts.

The clinical and demographic characteristics of patients undergoing TAVI pose unique challenges for developing and implementing optimal antithrombotic therapy. Ischaemic and bleeding events in the periprocedural period and months after TAVI still remain a relevant concern to be faced with optimised antithrombotic therapy. Moreover, the antiplatelet and anticoagulant pharmacopeia has evolved significantly in recent years with new drugs and multiple possible combinations. Dual antiplatelet therapy (DAPT) is currently recommended after TAVI with oral anticoagulation (OAC) restricted for specific indications. However, atrial fibrillation (which is often clinically silent and unrecognised) is common after the procedure and embolic material often thrombin-rich. Recent evidence has therefore questioned this approach, suggesting that DAPT may be futile compared with aspirin alone and that OAC could be a relevant alternative. Future randomised and appropriately powered trials comparing different regimens of antithrombotic therapy, including new antiplatelet and anticoagulant agents, are warranted to increase the available evidence on this topic and create appropriate recommendations for this frail population. Meanwhile, it remains rational to adhere to current guidelines, with routine DAPT and recourse to OAC when specifically indicated, whilst always tailoring therapy on the basis of individual bleeding and thromboembolic risk.