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RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS: WHAT IS THE BENEFIT?

RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS: WHAT IS THE BENEFIT?. Case presentation Neurology Rotation Rajwant Minhas April 2012. Outline. Learning Objectives Case Background: ALS Clinical Question Results Assessment Plan Monitoring Follow up. Learning Objectives.

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RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS: WHAT IS THE BENEFIT?

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  1. RILUZOLE FOR AMYOTROPHIC LATERAL SCLEROSIS: WHAT IS THE BENEFIT? Case presentation Neurology Rotation Rajwant Minhas April 2012

  2. Outline Learning Objectives Case Background: ALS Clinical Question Results Assessment Plan Monitoring Follow up

  3. Learning Objectives Be able to describe Amyotrophic Lateral Sclerosis in regards to: Incidence Pathophysiology Signs/Symptoms Discuss management of ALS Discuss the evidence behind efficacy and safety of Riluzole

  4. 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

  5. Review of Systems 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

  6. Patient Information 6

  7. Current Medications

  8. Medical Problem List ALS Neuropathic Pain

  9. 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

  10. 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

  11. Amyotrophic Lateral Sclerosis 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.

  12. Symptoms of ALS Weakness in limb and bulbar muscles Limb onset is most common (~80%) followed by Bulbar (~20%) and respiratory onset (~1%)

  13. 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

  14. 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

  15. Non-curable disease Is there anything we can use to slow disease progression?

  16. Riluzole Inactivated Decreases glutamate release 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

  17. 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?

  18. 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

  19. 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

  20. 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

  21. Cochrane Review Primary outcomes: Pooled hazard ratio based on % mortality (or tracheostomy) for 100 mg riluzole vs. placebo over all time points Secondary outcomes: Risk ratios (RRs) based on % mortality at 12,18 months for 100 mg riluzole vs. placebo RRs based on % mortality as function of time at 12 months: all doses of riluzole vs. placebo Muscle strength assessed by manual muscle testing Functional scales Quality of life of patients and caregivers Adverse effects from riluzole

  22. More advanced disease

  23. Yanagisawa 1997 Igakuno Ayumi 1997;182:851-66. 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 24

  24. 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

  25. 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

  26. 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

  27. Results: Safety

  28. 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

  29. 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

  30. Review Systematic review Objective: To assess the potential benefits and harms of riluzole 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.

  31. Canadian Coordinating Office for Health Technology Assessment; 2003. Technology report no 37.

  32. 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 report no 37.

  33. 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

  34. 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 (Journal of the Neurological Sciences 272 (2008) 60-70)

  35. Recommendations Continue with current regimen of Riluzole

  36. 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

  37. Monitoring

  38. Questions ?

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