1 / 30

Michelle R. Johnson, MD Journal Club November 13, 2015

Effect of Dextromethorphan- Quinidine on Agitation in Patients with Alzheimer Disease Dementia A Randomized Control Trial. Cummings JL, Lyketsos CG, Peskind ER, et al. JAMA. 2015;314(12):1242-1254. Michelle R. Johnson, MD Journal Club November 13, 2015. www.alma3rifaplus.com. Case.

mcallisterw
Télécharger la présentation

Michelle R. Johnson, MD Journal Club November 13, 2015

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Effect of Dextromethorphan-Quinidine on Agitation in Patients with Alzheimer Disease DementiaA Randomized Control Trial Cummings JL, Lyketsos CG, Peskind ER, et al. JAMA. 2015;314(12):1242-1254. Michelle R. Johnson, MD Journal Club November 13, 2015 www.alma3rifaplus.com

  2. Case 77 y/o Caucasian F home care patient with hx of dementia of the Alzheimer’s type, HTN, DM, severe osteoarthritis seen at home after family reported increasing aggressive behaviors. Daughter is exhausted, worried she can no longer care for her at home. Notable meds include donepezil, memantine, celexa 10mg and seroquel 12.5mg prn (uses rarely), all of which had been effective up until the past few weeks. http://www.seniorennet.nl/

  3. Background • Agitation in Alzheimer’s disease (AD) is common (>90%), persistent, difficult to treat • Agitation/aggression associated with patient caregiver distress, greater risk of institutionalization, accelerated progression to severe dementia & death • Current treatments are effective but risky • Antipsychotics - increased mortality, CV events, sedation, falls, cognitive impairment, metabolic syndrome, EPS, tardive dyskinesia • SSRIs - prolonged QTc and mild cognitive decline (citalopram)

  4. Citalopram in AD • Cochrane Systematic Review (Seitz et al, 2011): sertraline & citalopram associated with reduction in agitation sx compared to placebo in 2 studies • Effect of citalopram on agitation in AD: the CitAD randomized clinical trial (Porsteinsson et al, JAMA 2014) • 186 participants, 9wk of therapy (dose up to 30mg) vs placebo • Clinically meaningful reduction in agitation comparable to that seen with antipsychotics • Secondary outcomes - total NPI score, individual NPI domains, NPI caregiver distress ratings • Assoc with mild cognitive effects & prolonged QTc ≥ 30 ms from baseline to week 3 at this dose

  5. Antipsychotics in AD • Systematic Review (Seitz et al, 2013): risperidone, olanzapine & aripiprazole show evidence of benefit but assoc with death, stroke, falls, sedation & cognitive decline • Cochrine Systematic Review (Ballard et al, 2006): improvement in aggression with risperidone & olanzapine compared to placebo but assoc with CV events & EPS

  6. Antipsychotics in AD • Meta-analyses (Schneider et al, 2005): atypicals assoc with increased risk of death, OR of 1.54 • Pooled Analysis 3 RCTs of NH residents (De Deyn et al, 2005): largest database of double-blind RTCs support risperidone’s efficacy & safety, well tolerated with respect to EPS, somnolence & anticholinergic effects

  7. Background • Dextromethorphan-quinidine (Nuedexta) • Approved in U.S. and Europe for treatment of pseudobulbar affect (involuntary/uncontrollable episodes of crying +/- laughing) • Cases of improvement of agitation in pts with dementia • Mechanism of Action • Serotonin and norepinephrine reuptake inhibitor • Low-affinity N-methyl-D-aspartate receptor antagonist

  8. Background • Dose of dextromethorphan and quinidine • Dextromethorphan antitussal dose: 10-20mg q4h • Quinidine antiarrhythmic dose: 300-600mg q8-q12h • Pseudobulbar affect treatment dose: 20/10mg BID • Treatment group I this study received max dose of dextromethorphan-quinidine 30/10mg BID

  9. Objective To assess the efficacy, safety and tolerability of dextromethorphan-quinidine as compared to placebo for moderate to severe agitation associated with Alzheimer disease http://thehealthdigest.org/1072/retaining-a-forgotten-past-in-dementia-village/

  10. Methods • Randomized, double-blind, placebo controlled clinical trial • Sequential parallel comparison design method • 10 week trial, 2 consecutive 5 week stages • Stage 1: randomized 3:4 to receive dextromethorphan-quinidine vs matching placebo • Stage 2: placebo group stratified by treatment response and re-randomized in a 1:1 ratio to receive therapy vs placebo

  11. Methods • Need a sample size of 196 patients to provide 90% power to detect a mean difference of 2.5 points • 220 pts randomized and comprised modified intention-to-treat analysis, 194 completed study • Dextromethorphan-quinidine n = 93, placebo n =127 (stage 1 baseline) • 152 pts received dextromethorphan-quinidine and 127 received placebo at some point during the study

  12. Intervention • Dextromethorphan-quinidine group • Week 1: dextromethorphan-quinidine 20/10mg once daily in morning, placebo in evening • Week 2-3: 20/10mg BID • Week 4-5: 30/10mg BID • Weeks 6-10: coinued nt 30/10mg BID if initial stage 1 group, new additions for stage 2 from rerandomization of placebos had similar 5wk uptitration as above • Placebo • Identical in appearance to therapy • Frequency BID

  13. Outcomes & Measures • Primary Outcome • Change in Neuropsychiatric Inventory (NPI) Agitation/Aggression domain score (range 0 to 12) • Secondary Outcomes • NPI total score (range 0-144) • Individual NPI domain scores (range 0-12) • NPI composite scores (NPI4A, NPI4D) • NPI Caregiver Distress score for each positively endorsed NPI domain (range 0-5) • ADCS Activities of Daily Living Inventory (range, 0-54) • Cornell Scale for Depression in Dementia (range 0-38)

  14. Outcomes & Measures • Secondary Outcomes (cont..) • Caregiver Strain Index (range 0-13) • Quality of Life–Alzheimer Disease score (range 13-52) • Psychotropic medication changes/rescue use of lorazepam • Cognition (MMSE and AD Assessment Scale–Cognitive Subscale) • Measuring clinical meaningfulness • Alzheimer Disease Cooperative Study (ADCS) Clinical Global Impression of Change scores (range 1-7) • Patient Global Impression of Change scores rated by caregiver (range 1-7) • Assessed at weeks 5 and 10

  15. What is the NPI? • Most widely used, well-validated behavior instrument in clinical trials of antidementia agents • Translations available in >40 languages and dialects • Each behavior domain is scored (by the caregiver) for frequency, severity and associated caregiver distress • Hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep and night time behavior change, appetite/eating change

  16. Eligibility Inclusion Criteria Exclusion Criteria Non-AD dementia or agitation Mental health hospitalization Significant depression, bipolar, schizophrenia or schizoaffective Myasthenia gravis Cardiac disease prolonged QTc, complete heart block, torsades unexplained syncope in last yr Clinically sign/unstable disease Substance/etoh abuse within 3yr Taking 1st gen antipsychotics, tricyclic and MAO inhibitors • Age 50 - 90 • Probable Alzheimer disease • MMSE score 8-28 • Clinically significant agitation: • Interfered with daily routine • Warrants pharmacological tx • Mod agitation score (CGIS ≥4) • Doses were to remain stable • Stable doses of AD meds for ≥2mo • Stable doses of antidepressants, antipsychotics or hypnotics for ≥1mo were allowed

  17. Baseline Characteristics • 42 U.S. sites (outpatient AD clinics, ALF, NH • 88% community dwelling • 12-17% with hx of falls • Mean age of 77.8 (>65% were ≥75 yr) • ~55% women • >90% non-Hispanic white • MMSE ~17 https://onmogul.com

  18. Baseline Characteristics • Concomitant meds • Antidepressants (61% tx group vs 51% placebo) • Antipsychotics (17% tx group vs 22% placebo) • Benzos (6.5% tx group vs 9.5% placebo) • Rating scales • CGIS agitation score ~4.5 • NPI Agitation/aggression domain ~7.0 • NPI Total score~40

  19. Table 1

  20. Results • Primary End Point • Dextromethorphan-quinidine significantly improved the NPI Agitation/Aggression score in the primary sequential parallel comparison design analysis • ordinary least squares z statistic, -3.95; p<.001 • mean 50.7% reduction in scores from baseline to wk 10 compared to 26.4% treated with only placebo (p=.001) • Stage 1: Scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and 7.0 to 5.3 with placebo • least squares mean tx difference of -1.5 (95%CI, -2.3 to -0.7; p<.001) • Stage 2: Scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo • least squares mean tx difference of -1.6 (95%CI, -2.9 to -0.3; p=.02)

  21. Results • Secondary End Points • Statistically significant improvement favoring therapy • NPI total score • Caregiver Strain Index • ADCS Clinical Global Impression of Change score for agitation: 45% of therapy pts had ”moderate or marked improvement” vs 27.1% of placebo participants • Patient Global Impression of Change • No significant improvement for ADCS Activities of Daily Living Inventory, Quality of Life Alzheimer Disease score or cognition • Lorazepam rescue use • 6.6% (10/152) of pts in therapy group and 10.4% (13/125) of pts in placebo group

  22. Adverse Events Most common treatment-emergent adverse events of dextromethorphan-quinidine (>3% and greater than placebo) • Falls (8.6% vs 3.9%) • Diarrhea (5.9% vs 3.1%) • UTI (5.3% vs 3.9%) • Dizziness (4.6% vs 2.4%)

  23. Strengths • Magnitude of benefit for reducing agitation/aggression compares favorably with previous studies • Sample size similar to other major agitation studies • Primary end point - NPI, a well-validated instrument • Sequential parallel comparison design minimized placebo response (substantial in studies of agitation in AD) • Statistical benefit for both separate analysis for each of 5wk periods and combined overall analysis Ballard et al, JAMA Sept 2015

  24. Limitations • Total NPI is well validated however single NPI domain of Agitation/Aggression is not • Minimally clinically important difference (MCID) has not been established for this domain • Difficult to interpret the 1.5 point benefit between groups • Total NPI score benefit was statistically significant but did not achieve suggested threshold for MCID • Possibly too short to demonstrate improvement quality of life, adverse effects Ballard et al, JAMA Sept 2015

  25. Discussion • Funding from Avanir Pharmaceuticals • If true benefit, patients could remain in community longer • Safety profile is reasonably well understand as already FDA approved for pseudobulbar affect • Risks are potential for prolongation of QTc, falls, fatigue, dizziness, diarrhea, serotin syndrome if combined with SSRI, potential anticholinergic effects • Need additional independent studies with longer duration to confirm treatment effect and adverse effects

  26. Back to the Case • Increased celexa from 1020mg • Daughter noted improvement within few weeks • Last EKG 8/2013 QTc of 445ms, LAFB, PACs • Need to repeat EKG • Call to nurse case manager this week re: increased aggression in late afternoons and paranoia re: husband infidelity, gave seroquel 12.5mg x1 for several nights with good effect • Based on this study, should I trial this therapy?

  27. References • Aalten P, Verhey FR, Boziki M, et al. Neuropsychiatric syndromes in dementia: results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007; 24(6) 457-463. • Ballard C, MD; Sharp S, BSc; Corbett A, PhD. Editorial – Dextromethorphan and Quinidine for Treating Agitation in Patients with Alzhieimer Disease Dementia. JAMA, September 2015: 314 (12), 1233-1235 • Ballard C, Waite J.The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476. Review. PMID:16437455 • Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia A Randomized Clinical Trial. JAMA. 2015;314(12):1242-1254. doi:10.1001/jama.2015.10214. • Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008191. doi: 10.1002/14651858.CD008191.pub2 • Seitz DP, Gill SS, Herrmann N, Brisbin S, Rapoport MJ, Rines J, Wilson K, Le Clair K, Conn DK. Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic review. Int Psychogeriatr. 2013 Feb;25(2):185-203. doi: 10.1017/S1041610212001627. Epub 2012 Oct 19

  28. Thank you • Gary Brandeis, MD • Won Lee, MD • Nuala McDonough, RN • Christine Liu, MD • Alan Mandell, MD rantingsofaloon.wordpress.com

  29. Questions? www.empowher.com

More Related