The Top Articles of 2014 Dov Gandell MDCM, FRCPC October 31, 2014.
Disclosure Statements Faculty: Dov Gandell Relationships with commercial interests: No commercial or industry disclosures
Final assessment: trick or treat? Treat a positive result that is valid and may influence practice Trick a negative result that does not terminate that area of investigation Empty wrapper a positive result with validity or safety concerns
Methods: article selection Canvassed division members, University of Toronto Geriatric Medicine Dr. Shabbir M.H. Alibhai and Dr. Rajin Mehta Scanned table of contents and read major journals Scanned and read journal review publications Reviewed articles presented at the Geriatric Medicine Journal Club
Methods: article selection Influence or understanding of daily practice Quality of the evidence Randomized controlled trial (RCT) Range of geriatric medicine syndromes Cognition (mild cognitive impairment, dementia, delirium) Frailty/mobility Medication appropriateness Lifestyle interventions
N Engl J Med 2013;368:1279-90
Randomized, single-blind, controlled trial Intervention Mediterranean diet supplemented with 1L per week extra virgin olive oil Mediterranean diet with 30 grams of nuts (walnuts, almonds, and hazelnuts) Control diet, low fat No total calorie restriction advised nor was physical activity promoted Median follow-up 4.8 years N = 7447 High-risk adult, primary prevention Primary Outcome Composite of myocardial infarct, stroke, and death from cardiovascular causes N Engl J Med 2013;368:1279-90
Inclusion 55 80 years old Type II diabetes mellitus or 3 major cardiovascular risk factors Smoking, hypertension, elevated LDL, low HDL, obesity, or a family history of premature CAD Average participant 67 years old Spanish female Hypertension Hyperlipidemic BMI > 25 50% were diabetic N Engl J Med 2013;368:1279-90
Results Crude rate per 1000 patient/years 8.1 (6.6 9.9) med diet plus EVOO versus 11.2 (9.2 13.5), p = 0.009 8.0 (6.4 9.9) med diet plus nuts versus 11.2 (9.2 13.5), p = 0.02 Adverse events Not reported TREAT Strengths It is reasonable to recommend the Mediterranean diet for primary prevention of cardiovascular disease in high risk seniors Randomized trial design for dietary intervention with a large sample size Length of follow-up Weaknesses/Discussion Change in control intervention midway through the trial More attrition in the control group Statistically significant result but small effect size Generalizability to the North American population unknown N Engl J Med 2013;368:1279-90
JAMA 2014;311(23):2387-2396
Single-blind, randomized controlled trial Intervention Physical activity intervention 150 min/wk strength, flexibility, and balance training versus Health education program weekly workshops x 26 weeks, monthly thereafter Mean follow-up 2.7 years N = 1635 Pre-frail older adults Primary Outcome Major mobility disability loss of the ability to walk 400m in 15 minutes (without sitting or the help of another person or a walker) JAMA 2014;311(23):2387-2396
Inclusion Sedentary less than 20min/week of physical activity Frail Short Physical Performance Battery (SPPB) < 9 Able to walk 400 m in less than 15 minutes Average participant 79 years old Caucasian female BMI 30 SPPB score of 7.3 Walking speed of 0.83 m/s JAMA 2014;311(23):2387-2396
Results 30.1% intervention versus 35.5% control, HR 0.82 (0.69 0.98), p=0.03 Major mobility disability or death 32.3% intervention versus 37.8% control, HR 0.82 (0.70 0.97), p=0.02 Adverse events No difference Strengths TREAT 150 minutes of exercise weekly helps prevent mobility disability in older adults Large sample or pre-frail older adults with more than 2 years of follow-up 400 metre walk test correlated to gait speed which is associated with mortality Weaknesses/Discussion Functional outcomes were not reported Highly motivated, self-selected sample Intensive intervention and difficult outcome measure for most settings JAMA 2014;311(23):2387-2396
N Engl J Med 2014;370:311-21
EXPEDITION 1 and EXPEDITION 2 Double-blind, placebo-controlled, randomized trials (Phase 3) Intervention Solanezumab 400mg IV Q4weeks versus placebo 18 months N = 1012, 1040 Mild to moderate Alzheimer s disease Primary Outcomes Cognition: Alzheimer s Disease Assessment Scale (ADAS-Cog 11) Range 0 70 with higher scores indicating greater impairment Function: Alzheimer s Disease Cooperative Study/Activities of Daily Living Scale (ADCS-ADL) Range 0 78 with lower scores indicating greater impairment N Engl J Med 2014;370:311-21
Inclusion/exclusion > 55 years old Mild to moderate Alzheimer s disease - Folstein Mini Mental Status Exam (FMMSE) 16 26/30 Absence of depression Geriatric Depression Scale (GDS) 6 Otherwise healthy Average participant 74 years old Caucasian, female 12 years education Folstein mini mental status exam score 21/30 Taking a cholinesterase inhibitor alone or in combination with memantine N Engl J Med 2014;370:311-21
Results Cognition: ADAS Cog 11-0.8 (95% CI -2.1 0.5; p = 0.24) Function: ADCS ADL -0.4 (95% CI -2.3 1.4; p = 0.64) Adverse effects no significant differences Silver lining Biomarker results positive Pre-specified secondary analysis in mild disease revealed benefit More to come TRICK Despite the negative result from this trial, passive immunotherapy for mild Alzheimer s disease remains under investigation Solanezumab in mild AD, phase 3 December 2016 Crenezumab, two phase 2 trials (ABBY/BLAZE) data in abstract form presented July 2014 Gantenerumab July 2018 N Engl J Med 2014;370:311-21
JAMA 2014;311(1):33-44
Double-blind, placebo controlled, randomized trial Intervention Alpha-tocopherol 2000 IU daily Memantine titrated to 10 mg twice a day Alpha tocopherol and memantine, above doses Mean follow-up 2 years N = 613 Mild to moderate Alzheimer s disease Primary Outcome Function: Alzheimer s Disease Cooperative Study/Activities of Daily Living (ADCS ADL) scale Range 0 78 with lower scores indicating greater impairment JAMA 2014;311(1):33-44
Inclusion/exclusion Veterans with mild to moderate Alzheimer FMMSE 12 26/30 Taking a cholinesterase inhibitor Average participant 79 years old Caucasian man More than high school education FMMSE score 21/30 Cholinesterase inhibitor JAMA 2014;311(1):33-44
Results 3.15 units ADCS ADL inventory less decline alpha tocopherol versus placebo (95 CI 0.92 5.39, p = 0.03) Adverse effects No significant differences Strengths Duration of follow-up Outcome measures Weaknesses/Discussion Empty wrapper Vitamin E, given the sum of evidence in AD and in light of potential adverse effects, should not be routinely prescribed for Alzheimer s disease patients Most positive AD intervention trials reveal cognitive benefit, not function Unclear why memantine and vitamin E arm did not reveal benefit Safety risk platelet inhibition, cardiac outcomes, cancer risk JAMA 2014;311(1):33-44
CMAJ 2014. DOI:10.1503 cmaj/140495
Multicentre, double-blind randomized controlled trial Intervention Melatonin 3mg HS for 5 consecutive days, starting within 24 hours after admission versus placebo N = 452 Patients scheduled for acute hip surgery Primary Outcome Incident delirium within 8 days of admission Delirium determined by DSM IV criteria CMAJ 2014. DOI:10.1503 cmaj/140495
Inclusion 65 years old Emergent hip fracture surgery Exclusion Delirium on admission Already taking melatonin Average participant 84 years old Dutch female Admitted from home CMAJ 2014. DOI:10.1503 cmaj/140495
Results Incident delirium 29.6% melatonin versus 25.5% placebo (95% CI -0.05 13.1) No difference mortality, cognitive, functional outcomes at 3 months Delirium duration shorter in melatonin group Adverse effects not reported Strengths TOOTHBRUSH A large RCT did not demonstrate any benefit of melatonin in preventing post-operative Large sample size for a delirium study Sample representative of typical delirium hip fracture patients Long term follow-up data Weakness Apparent randomization failure more patients with previous delirium in melatonin group CMAJ 2014. DOI:10.1503 cmaj/140495
N Engl J Med 2014;370:2467-77
Multicenter, randomized controlled trial Intervention 30-day event-triggered recorder versus 24 hour holter monitor N = 572 Cryptogenic ischemic stroke or TIA Primary outcome 30 seconds of atrial fibrillation within 90 days of randomization N Engl J Med 2014;370:2467-77
Inclusion 55 years old Cryptogenic ischemic stroke or TIA diagnosed by a stroke neurologist Event within 6 months of enrollment Minimum investigations: 24 hour ambulatory holter, ECG, echocardiogram, brain and neurovascular imaging Average participant 73 years old Caucasian male Ischemic stroke CHADS 2 score 3 75 days from event N Engl J Med 2014;370:2467-77
Results 16.1% intervention group versus 3.2% control group (95 CI 8.0 17.6), p<0.001 18.6% intervention group versus 11.1% control group had anticoagulation prescribed (95 CI 1.6 13.3), p =0.01 Strengths TREAT Patients with ischemic cryptogenic stroke or TIA should receive prolonged cardiac monitoring to diagnose atrial fribrillation Highly representative patient sample Weaknesses/Discussion Point estimate of detected atrial fibrillation likely an underestimate large strokes excluded Intracranial imaging and transesophageal ultrasound not done as part of work-up N Engl J Med 2014;370:2467-77
JAMA Intern Med. 2014;174(6):890-898
Cluster randomized controlled trial Eliminating Medications Through Patient Ownership of End Results (EMPOWER) Intervention 8 page booklet based on self-efficacy theory Self assessment on the risks of benzodiazepine use, presentation of the evidence for benzodiazepine-induced harms, knowledge statements to create cognitive dissonance about safety of benzodiazepine use, education about drug interactions, peer champion stories, suggestions for therapeutic substitutes for insomnia or anxiety, and step-wise tapering recommendations (visual 21 week tapering protocol Usual care N = 30 community pharmacies, 303 patients randomized Primary Outcome Complete cessation of benzodiazepine use in the 6 months following randomization JAMA Intern Med. 2014;174(6):890-898
Inclusion/Exclusion criteria 65 years old Minimum of 5 active prescriptions One prescription for a benzodiazepine (short, intermediate, long) Benzodiazepine dispensed for at least 3 consecutive months before screening Dementia, psychiatric illness excluded Average participant 75 years old Female Benzodiazepine prescribed for either insomnia or anxiety Benzodiazepine use for a mean of 10 years Average daily dose was 1.3 mg of lorazepam JAMA Intern Med. 2014;174(6):890-898
Results Complete cessation of benzodiazepine 27% intervention versus 5% controls, prevalence difference 23% (14 32%) Odds Ratio 8.3 (3.3 20.9) NNT for complete cessation or a dose reduction was 3.7 Adverse effects Rebound insomnia or anxiety occurred in 42% but no differences in major adverse effects Strengths Direct to patient education approach TREAT Direct to patient education helps reduce inappropriate benzodiazepine use Data from older adults in benzodiazepine cessation trial Weaknesses No true control general medication education not provided to usual care Patients may have obtained benzodiazepine prescriptions from other pharmacies Follow-up relatively short JAMA Intern Med. 2014;174(6):890-898
BMJ 2013;346:f2570
Cluster randomized controlled trial Long term follow-up of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) Intervention Depression care manager working with the primary care physician to provide algorithm based care versus usual care N = 20 primary care practices, 1226 patients Primary Outcome Mortality risk Median follow-up of 98 months (0.8 116 months) BMJ 2013;346:f2570
Inclusion Age 60 English speaking Mini mental status exam score > 17 Depression diagnosed with DSM IV criteria Average participant 71 years old Single female 13 years education MMSE score 28/30 Hamilton Depression Rating Score (HDRS) 21 major depression 5 not depressed BMJ 2013;346:f2570
Results Patients with major depression Usual care practices Mortality risk HIGHER HR 1.90 (95 CI 1.57 2.31) than those without depression Intervention practices Mortality risk SIMILAR HR 1.09 (95 CI 0.83 1.44) than those without depression. Intervention versus usual care practices Mortality risk LOWER Strengths HR 0.76 (95 CI 0.57 1.00; p=0.05) than those without depression Length of the follow-up period TREAT Hard outcome evidence to support the need for better mental health care for older adults Weaknesses Small sample size most RCTs that demonstrate mortality benefit are much larger Suboptimal control Confidence interval includes 1 needs replication BMJ 2013;346:f2570
J Am Geriatr Soc 62:857-864, 2014
Meta-analysis To evaluate the safety and efficacy of novel oral anticoagulants (NOACs) in elderly patients, defined as age 75 10 RCTs (dabigatran 2, rivaroxaban 5, apixiban 3) N = 25 031 TREAT Risk of major or clinically relevant bleeding NOACs vs conventional therapy Precise risk of adverse events with NOACs likely to come with post-marketing surveillance 6.4% vs 6.3%; OR 1.02 (95 CI 0.73 1.43) Risk of major or clinically relevant bleeding NOAC vs warfarin 6.5% vs 7.1%; OR 0.76 (95 CI 0.51 1.12) Risk of stroke and systemic embolism NOAC vs warfarin 3.3% vs 4.7%; OR 0.65, 95 CI 0.48 0.87. NNT 71 J Am Geriatr Soc 62:857-864, 2014
Ahmed et al. J Am Geriatr Soc 62:410-411,2014 Kahan et al. CMAJ 2014.DOI:10.1503/cmaj.131821
Medicinal marijuana in older adults April 1 st, 2014. Health Canada approves Dried cannabis for purchase from a licensed distributor Physican s prescription required daily dose and monthly quantity Dried cannabis use in older adults 6.5% 61 to 76 years old 31 country survey, including Canada 37% 61 to 93 years old among 5500 prescription cannabis users in the Netherlands Ahmed et al. J Am Geriatr Soc 62:410-411,2014 CMAJ 2014. DOI:10.1503/cmaj.131821
Medicinal marijuana in older adults The evidence N = 12, mean age 72.7 Severe Alzheimer s disease Dronabinol 2.5mg/d Anorexia and behavioural disturbance improved N = 2, 75- and 81- year old men Alzheimer s disease Dronabinol 2.5mg/d Reduced night time agitation J Clin Psychopharm 31(2);256-257, 2011 Int J Geriat Pxychiatry 12;913-919, 1997
Medicinal marijuana in older adults Risks Perceptual, motor, cognitive, functional, lung toxicity, driving Standard analgesics and synthetic oral cannabinoids trial first Clear indications neuropathic pain spasticity from multiple sclerosis Ahmed et al. J Am Geriatr Soc 62:410-411,2014 CMAJ 2014. DOI:10.1503/cmaj.131821
TRICK 2014 brought no evidence to support the use of marijuana in older adults but prescriptions can now be written and patients may request them
Thank you
Identify the correct statement A) a large RCT has established the benefit of melatonin to reduce incident delirium in hip fracture patients B) multiple large RCTs of passive immunotherapy for Alzheimer s dementia reveal positive intermediate outcomes C) vitamin E should be prescribed for Alzheimer s disease patients D) the MoCA, applied properly, has high discriminative power to identify who will transition from MCI to overt dementia
Identify the correct statement A) a large RCT has established the benefit of melatonin to reduce incident delirium in hip fracture patients B) multiple large RCTs of passive immunotherapy for Alzheimer s dementia reveal positive intermediate outcomes C) vitamin E should be prescribed for Alzheimer s disease patients D) the MoCA, applied properly, has high discriminative power to identify who will transition from MCI to overt dementia
Which statement is false? A) The Mediterranean diet has been shown to prevent secondary but not primary cardiovascular outcomes B) 2.5 hours of exercise per week can prevent major mobility disability in older adults C) The literature demonstrates patients can successfully discontinue benzodiazepines without a physician initiating or leading the change D) Treating major depression with algorithm based care can improve survival
Which statement is false? A) The Mediterranean diet has been shown to prevent secondary but not primary cardiovascular outcomes B) 2.5 hours of exercise per week can prevent major mobility disability in older adults C) The literature demonstrates patients can successfully discontinue benzodiazepines without a physician initiating or leading the change D) Treating major depression with algorithm based care can improve survival
To improve my practice, I will A) start writing prescriptions for medicinal marijuana for all my patients B) investigate cryptogenic ischemic stroke or TIA with prolonged cardiac rhythm monitoring C) prescribe novel oral anticoagulants regardless of creatinine clearance D) forget to share or discuss the tricks and treats with my colleagues
To improve my practice, I will A) start writing prescriptions for medicinal marijuana for all my patients B) investigate cryptogenic ischemic stroke or TIA with prolonged cardiac rhythm monitoring C) prescribe novel oral anticoagulants regardless of creatinine clearance D) forget to share or discuss the tricks and treats with my colleagues
Other articles of interest Demographic Characteristics and Healthcare Use of Centenarians: A Population- Based Cohort Study J Am Geriatr Soc 62:86-93,2014 A controlled evaluation of comprehensive geriatric assessment in the emergency department: the Emergency Frailty Unit Age and Ageing 2014;43:109-114 Montreal Cognitive Assessment Memory Index Score (MoCA MIS) as a Predictor of Conversion from Mild Cognitive Impairment to Alzheimer s Disease J Am Geriatr Soc 62:679-684,2014 The impact of first- and second-eye cataract surgery on injurious falls that require hospitalisation: a whole population study Age and Ageing 2014;43:341-346 Life-span cognitive activity, neuropathologic burden, and cognitive aging. Neurology 2013;81:314-321