Transcript Slide 1

RILUZOLE FOR
AMYOTROPHIC LATERAL
SCLEROSIS: WHAT IS THE
BENEFIT?
Case presentation
Neurology Rotation
Rajwant Minhas
April 2012
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Outline
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Learning Objectives
Case
Background: ALS
Clinical Question
Results
Assessment
Plan
Monitoring
Follow up
Learning Objectives
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Be able to describe Amyotrophic Lateral Sclerosis in
regards to:
– Incidence
– Pathophysiology
– Signs/Symptoms
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Discuss management of ALS
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Discuss the evidence behind efficacy and safety of
Riluzole
Patient Information
• GP 73 yo (175 cm, 67 kg) East-Indian Male
• Admitted Mar 21, 2011
• C/C: Drowsiness, weakness
• HPI:
– Had a fall 3 days PTA, slurred speech and unable to walk
– Fell 3 wks ago, right sided weakness
Review of Systems
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CNS: Temp = 37.7 C HEENT: Dysarthria
Resp:
– RR = 18, FVC (Sitting) = 16% of predicted, FVC (Supine) = 21% of predicted
– Significant diaphragmatic weakness and hypoventilation, orthopnea, dyspnea
CVS:
– BP = 107/60 mm Hg, HR = 76/min
GI/GU/Renal:
– SCr = 52, BUN = 4, eGFR >120
MSK/Skin/Extremities: Weakness, neuropathic pain
Date
Test
Results
April 4,
2012
Head MRI
Cervical spondylosis but no significant abnormality in cervical
spine
Mar 30,
2012
EMG
Clear motor neuropathy affecting bulbar, thoracic, cervical &
lumbar
March 21,
2012
Head CT
No evidence of acute infarction or hemorrhage
Patient Information
PMH
MPTA
•4 yr hx of weakness affecting all
regions including bulbar, thoracic,
cervical & lumbar
– New diagnosis of ALS
•BPH and urethral stenosis with a
previous dilatation of the urethra
Tamsulosin 0.4 mg PO daily
•HTN
Irbesartan/HCTZ (300
mg/25mg) PO daily
•GERD
Lansoprazole 30 mg daily
•Bilateral Knee replacement
•Mild central spinal stenosis
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Current Medications
HTN
Candesartan 8 mg PO daily
GERD
Pantoprazole 40 mg PO BID
BPH
Tamsulosin 0.8 mg PO daily
GI Motility
Metoclopramide 10 mg PO BID ½ H AC
DVT Prophylaxis
Dalteparin 5000 Units SC daily
Constipation
Sennosides 24 mg PO daily
Urinary Retention
Bethanechol 37.5 mg PO TID AC
Insomnia
Zopiclone 3.75-7.5 mg PO HS PRN
Heart burn
Al/Mg antacid 15-30 mL PO Q4H PRN
Fever/ Muscoskeletal Pain
Acetaminophen 325-650 mg PO Q4-6H PRN
Nausea
Dimenhydrinate 25-50 mg PO Q4H PRN
Medical Problem List
• ALS
• Neuropathic Pain
Drug Related Problems
• GP is experiencing symptoms of ALS
(slurred speech, left side weakness) and
would benefit from reassessment of
current drug therapy
• GP is experiencing neuropathic pain is his
feet and would benefit from reassessment
of current drug therapy
Amyotrophic Lateral Sclerosis
• A rapidly progressive neuromuscular
disease
• Neuronal death paralysis of voluntary
muscles
• Exact cause unknown
• Assumed glutamate (1° excitatory neuron)
plays a key role
– Toxic concs. in synaptic cleft result in
neuron destruction
• Most people die from respiratory failure
– Usually within 3 to 5 years from
symptom onset
– ~ 10% survive for >10 years
Amyotrophic Lateral Sclerosis
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Incidence: ~ 2 per 100,000 per annum
Prevalence: 25,000 pts in N. America
40 and 60 years of age most affected
Men > women
95% sporadic, remaining inherited
Affects all ethnic and socio-economic groups
Age and family history only established risk factors
Canadian Coordinating Office for Health
Technology Assessment; 2003. Technology
report no 37.
Symptoms of ALS
• Weakness in limb and bulbar muscles
– Limb onset is most common (~80%) followed by
– Bulbar (~20%) and respiratory onset (~1%)
Upper motor neuron symptoms
Lower motor neuron symptoms
Weakness
Weakness
Hyperreflexia
Hyporeflexia
Spasticity
Muscle atrophy
Loss of dexterity
Fasciculations (GP: tongue, entire
chest, thoracic, pectorals,
paraspinals)
Slowed movements
Muscle cramps
Hypotonicity or flaccidity
Diagnosis of ALS
• No definitive test
• Presence of upper and lower motor
neuron signs in a single limb is strongly
suggestive
• Electromyography (EMG)
– Detects electrical activity in muscles
Ethical Challenges
• Begins with breaking the news to patient
– Avoid being personal or dismissive
• Physical and emotional stress
• Use of life-sustaining therapies:
– Long term mechanical ventilation
– Feeding tube
• Symptomatic management options
• Surrogate decision makers
Non-curable disease
Is there anything we can
use to slow disease
progression?
Riluzole
Inactivated
• Only FDA-approved drug
available to treat
• Exact MOA unknown
• Shown to prolong survival by
several months, time to
tracheostomy or ventilation
support
• Does not reverse already done
damage
Decreases glutamate
release
The Controversy
Concerns about therapeutic effect persist:
• Modest prolongation of survival
• Relatively high cost (~ $12,000/year)
• Use in patients who do not fulfill the study entry
criteria (age <75, duration <5, Vital capacity >60% of
predicted value)?
– Use in tracheotomised patients?
• Stop at advanced stages of the disease. If so, when?
Clinical Question
P: In a 73 year old male diagnosed with ALS
with symptoms of 4 years
I: Riluzole 50 mg BID
C: Placebo
O: Slowing down disease progression,
prolonging survival and quality of life
Literature Search
• Search Terms:
– Riluzole, ALS
– Limitations: Adults, English
• Results:
– 1 Cochrane review
– 1 Canadian Coordinating Office for Health Technology
Assessment (CCOHTA) review
– National Institute for Clinical Excellence (NICE) review
Cochrane Review
• Objective:
– To examine the efficacy of riluzole in:
• Prolonging survival
• Delaying the use of surrogates (tracheostomy and
mechanical ventilation) to sustain survival
– Assess the effect of riluzole upon functional
health
Cochrane Review
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Primary outcomes:
1. Pooled hazard ratio based on % mortality (or tracheostomy)
for 100 mg riluzole vs. placebo over all time points
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Secondary outcomes:
1. Risk ratios (RRs) based on % mortality at 12,18 months for
100 mg riluzole vs. placebo
2. RRs based on % mortality as function of time at 12 months:
all doses of riluzole vs. placebo
3. Muscle strength assessed by manual muscle testing
4. Functional scales
5. Quality of life of patients and caregivers
6. Adverse effects from riluzole
Bensimon 1994
(Placebo/Riluzole)
Lacomblez 1996
Yanagisawa 1997
Bensimon 2002
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78/77
242/717
97/98
86/82
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Riluzole 100 mg
Riluzole 50 mg, 100 mg,
200 mg
Riluzole 100 mg
daily
Riluzole 50 mg
BID
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Placebo
Placebo
Placebo
Placebo
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Survival and
changes in
functional status
after 12 months of
tx
Tracheostomy-free
survival (included death
from any cause),
tracheostomy, and
intubation with artificial
ventilation leading to
tracheostomy)
Disease
progression utilizing
multiple measures
(walking, arm
function,
tracheostomy,
ventilation, tube
feeding
Time to failure
(considered to
be death,
tracheostomy or
intubation with
artificial
ventilation)
More
advanced
disease
Yanagisawa 1997
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P: 195 patients in Japan
I: Riluzole 100 mg daily
C: Placebo
O: Disease progression utilizing multiple measures
(walking, arm function, tracheostomy, ventilation,
tube feeding)
• Full data on tracheostomy-free survival not
available
• Excluded from Cochrane meta-analyses
Igakuno Ayumi
1997;182:851-66.
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Results
• 1⁰ outcome measure: pooled HR based on % mortality
(or tracheostomy) from 3 trials over all time points
• Riluzole 100 mg slight benefit for the homogenous
group of patients in the first 2 trials,
– P=0.042, HR 0.80, CI 0.64 to 0.99
– No evidence of heterogenity (P=0.33)
• Median survival:
– Riluzole = 15.5 months
– Placebo = 13.2 months
Results
• On addition of Bensimon 2002 trial
– Evidence of heterogeneity (P < 0.0001)
• Overall tx effect ↓ but still significant (HR 0.84, 95% CI 0.698-0.997, P
value =0.046)
• 9% gain in the probability of surviving 1 year (49% in the placebo and 58%
in the riluzole group), ↑ median survival from 11.8 to 14.8 months
• ARR with the 100 mg dose @ 12 months = 9%.
• NNT to delay 1 death until after 12 months = 11
• Small beneficial effect on both bulbar and limb function, but not on
muscle strength
Pooled Survival Time in Months
HR from all 3 trials: 16% ↓ in the HR
Not quite statistically significant (P=0.056)
A 10% absolute ↑ in the probability of
survival for 1 year (56% in placebo group
and 66% in the riluzole group)
Solid lines: Pooled results from
2 trials that were homogeneous
Results: Safety
Study
Adverse Effect
Combination of 3 trials
Nausea, Asthenia
Vomiting, diarrhea, anorexia and dizziness
somewhat more frequent in Riluzole but did not
reach statistical significance
↑ ALT
No serious adverse effects from Riluzole in any
study
Cochrane Review: Conclusion
• Riluzole 100 mg daily prolongs median
survival by 2-3 months in patients with:
– Probable and definite ALS with symptoms <5
years, FVC >60%, age < 75 yrs
– Reasonably safe
– More studies required in older patients and
those with more advanced disease
NICE Review: Conclusion
• Limited evidence of benefit in tracheostomy-free
survival = combined endpoint of time to
tracheostomy + death
• At best, riluzole postpones death for a few months
without precluding the need for supportive care and
practical help
• Retrieved the tracheostomy-free survival results of
Yanagisawa 1997 trial
– Overall conclusion similar as Cochrane’s
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Review
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Systematic review
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Objective: To assess the potential benefits and harms of riluzole
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Outcomes:
– All-cause mortality and tracheostomy-free survival
– All-cause morbidity
– Patient withdrawals due to adverse events
– Number of patients experiencing adverse events
– Quality of life
– Time to tracheostomy
• Focuses on all-cause mortality, morbidity (including
drug-related morbidity) or the quality of life.
Canadian Coordinating Office for Health
Technology Assessment; 2003. Technology
32
report no 37.
Conclusions
• Potential to ↓ serious morbidity in some
patients at the cost of causing some drug
intolerance (withdrawals due to adverse
events)
• No information to describe its impact on
QoL or time to tracheostomy alone.
• More adequate reporting of adverse
events required
Canadian Coordinating Office for Health
Technology Assessment; 2003. Technology
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report no 37.
Limitations of Studies
• Small population size
• Relatively short duration (12 to 18 months)
• No information of quality of life, time to
tracheostomy
• Generalizability of findings uncertain: 363 of 1477
patients (25%) in RCTs were either older, had
more advanced disease or were Japanese
• Few North American patients were included
Implications to Practice
• More studies required to examine the effect on:
– QoL
– Functionality
– In different subgroups (older and more severe
patients vs. mild and younger patients)
• Survival data: 50-month survival data but these data
unavailable
• Ethnicity of our patient
– Indians appear to have a relatively younger age of
onset, prolonged survival, relatively slow course
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(Journal of the Neurological Sciences 272 (2008) 60-70)
Recommendations
• Continue with current regimen of Riluzole
Follow-Up
• Depression: Mirtazapine 15 mg PO HS
• PEG tube placement: To maintain adequate fluid intake
• Respiratory complications: Tracheostomy, Intermittent positive
pressure ventilation [IPPV] or bilevel positive airway pressure
[BIPAP])
• Neuropathic pain: Gabapentin 100 mg PO TID
Amitriptyline 20 mg PO HS
• Swallowing status has deteriorated
Monitoring
Endpoint
Expected Change
Frequency
CNS depression
Improvement
Ongoing
Neutropenia
Absent
Once a week
LFTs ↑ in transaminases
Absent
Once a month
Nausea
Absent
Ongoing
Asthenia (abnormal physical weakness or lack No worsening
of energy)
Ongoing
Interstitial lung disease (Dyspnea, cough,
chest pain)
Ongoing
Absent
Questions
?