Dextromethorphan-Quinidine: not quite ready for prime time

We only chose one article for this month's #GeriMedJC.  It was a randomized controlled trial of dextromethorphan-quinidine for agitation in Alzheimer disease:

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA. 2015 Sep 22-29;314(12):1242-54. 

There was pretty much consensus that dextromethorphan-quinidine is not quite ready for prime time in the management of agitation in Alzheimer disease.  Among some important concerns raised were:

• trial was funded by pharma
• last-observation carried forward is not a recommended method for imputing missing data in dementia trials
• biases introduced by the choice of rescue medication, Lorazepam
• agitation in this trial lumped together verbal aggression, physical aggression, and non-aggressive activity (pacing, restlessness)
• mode of action

Thank you to all those who joined in the discussion:

If you missed out on the tweetchat, don't despair!  Download the transcript here.

See you on December 18, 2015 at 08:00 ET for the next #GeriMedJC!  Articles will be announced in advance by @GeriMedJC

Agitation. All behaviour has meaning.

Agitation.  All behaviour has meaning.  There is a never-ending search for some magical pill. But what must the experience be like for the person living with dementia?   This trial on Dextromethorphan-Quinidine for agitation in Alzheimer's disease doesn't necessarily answer this latter, probably more important question.  We will tackle this interesting trial at the next #GeriMedJC on November 27 at 08:00 ET / 13:00 GMT.

PMID: 26393847


Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA. 2015 Sep 22-29;314(12):1242-54. 

IMPORTANCE:
Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking.

OBJECTIVE:
To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation.

DESIGN, SETTING, AND PARTICIPANTS:
Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed.

INTERVENTIONS:
In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60).

MAIN OUTCOMES AND MEASURES:
The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]).

RESULTS:
A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.

CONCLUSIONS AND RELEVANCE:
In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated.

Are you a fan of Twitter journal clubs like us?

Are you a fan of Twitter journal clubs like us?

At the American College of Rheumatology 2015 Annual Meeting, #RheumJC shared their experience of running a Twitter journal club. The abstract is posted below and you can see a copy of their poster here.

#Rheumjc: Development, Implementation and Analysis of an International Twitter-Based Rheumatology Journal Club

Background/Purpose: Twitter is an increasingly popular platform for discussion and engagement amongst healthcare professionals. Here we describe the development, implementation and analysis of a rheumatology focused journal club on Twitter which utilizes the hashtag #RheumJC.

Methods: A #RheumJC development team was created, consisting of two academic rheumatologists, two private practice rheumatologists, and an adult/peds rheumatology Fellow in Training (FIT). A needs assessment survey was conducted to gauge interest and help define the structure of the proposed journal club, including preferred times and types of articles to be discussed. Prior to journal club sessions, requests were made for temporary open-access privileges to the article as well as invites to principal authors to participate. A total of 4 different journal clubs were conducted between January 29th and May 2nd, 2015, each consisting of two “live” one hour chats, occurring during the evening hours of GMT (European centric) and EST (Americas centric) respectively, as well as a full 24 hrs to allow for asynchronous participation. An analysis of the different sessions was performed to assess participant demographics and participation rates. A qualitative content analysis of the entire 96 hours of transcript (1927 tweets) was conducted with 6 coders assessing 363 tweets each (313 unique and 50 common). Inter-rater agreement was calculated using Krippendorff’s alpha. A second survey was conducted after the 4th journal club to assess participant satisfaction and identify additional strengths or barriers.

Results: In total, 133 individuals from 31 different countries participated in at least one #RheumJC session. While the majority of participants were rheumatologists, over 8 different medical fields were represented. There were 13 FIT and other trainees amongst the participants. 38 individuals participated in at least 2 different journal clubs, 16 participated in at least 3, and 8 individuals were present at all four. The mean number of tweets during each of the live journal clubs sessions (n=8) was 197 (166 unique tweets, 31 re-tweets). For 2 of the journal clubs, principal authors of the manuscript were able to participate. A qualitative content analysis (inter-rater agreement alpha =0.801) revealed that the majority of the conversation was relevant with 28% of the tweets addressing the article directly (in the spirit of a “traditional” journal club) and another 62% considered “on-topic” with tweets referencing personal experiences, opinions, and links to supporting literature. A survey conducted after the 4th journal club revealed that the majority (89%) of those who had participated were either satisfied or very satisfied with the #RheumJC initiative. Of interest, 11% of journal club participants indicated they had joined Twitter solely because of #RheumJC, and another 37% stated that #RheumJC had increased their use of Twitter as a tool for medical education.

Conclusion: #RheumJC is a novel and popular approach to the traditional medical journal club which brings together people from around the globe and across specialties to discuss current medical literature in rheumatology utilizing Twitter as a medium for medical education.


While you're at it, check out the cool poster from our #NephJC colleagues here and the abstract that presented at the 2015 American Society of Nephrology Kidney Week:

Participation in the Open, Online, Twitter-Based, Nephrology Journal Club, NephJC

Background: We established an online nephrology journal club, NephJC, in April 2014 that meets twice monthly to discuss emerging research and clinical practice guidelines. We invite content experts and manuscript authors to the discussion. The meeting occurs on the public forum Twitter, allowing any interested individual to join. The purpose of NephJC is to provide a recurring, academically-minded event on Twitter to help establish this communication channel as one for serious nephrology discourse. In addition, online journal clubs are becoming a critical route for post publication peer review. In order to assess the impact of NephJC we reviewed participation in the discussions over the first year.

Methods: We searched the Symplur analytics database for all tweets with the hashtag #NephJC from March 16, 2014 to June 2, 2015. We measured the numbers of participants, number of tweets and assessed participation over the first 27 NephJC sessions.

Results: From April 29th to June 2nd, 2015, 27 topics were discussed. 27 Chats were at 9PM Eastern for the Americas and starting Dec 18, 2014 a Europe and Africa chat was added at 8PM GMT. 10 GMT chats have been held, generally one day after the American chat. 1,022 Twitter accounts have used the hashtag #NephJC a total of 14,891 times. The median journal club chat has 41.5 (IQR 30.5-56.5) participants and 353.5 (IQR 268.5-633.5) tweets. The number of participants and tweets increased over time (P<0.01). The addition of the GMT chat was responsible for some of that growth (median number of tweets increased from 273 to 662.5, P<0.001, participants from 35 to 60.5, P<0.001).

Conclusions: NephJC has established itself as an integral part of the online digital mentorship curricula. The sustained usage and growth in participation of NephJC demonstrates the positive value of Twitter in medical education.

Make sure to engage in some other medical Twitter journal clubs out there: #RheumJC, #NephJC, #RespJC, etc.