Journal Update Dec. 2003

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Journal UpdateDec. 2003

• Michael Rotblatt, MD
• Olive View-UCLA / Sepulveda VA

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Topics

• Oral thrombin inhibitors (ximelagatran)
• Marijuana for muscle spasms
• Pharmaceutical Update

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Case 1

• Mr. T, a 59 yo M with chronic atrial fibrillation
  and a h/o stroke, is taking warfarin
• His INR is difficult to control (often 3),
  and he has trouble keeping frequent clinic
  appointments
• Your attending asks you, what do you know about
  the new oral direct thrombin inhibitors? I hear
  they are just as effective as warfarin, and can
  be used without coagulation monitoring

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Background

• Atrial fibrillation or high-risk/recurrent VT --
  warfarin lifelong
• Single low-risk DVT -- warfarin x 6-12 mo
• Recurrence rate 5-8/yr
• Decrease recurrence with warfarin (1-3), but
  annual risk of major hemmorrhage 1-4/yr
• Low-dose warfarin may decrease bleeding risk

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Ideal Anticoagulant Properties

• warfarin LMWH
• Rapidly inhibits thrombus formation -
  X
• Oral absorption X -
• No therapeutic monitoring - X
• No bleeding - -
• Minimal/no side effects (X) (X)
• Minimal/no drug interactions - X
• Inexpensive X -

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Direct Thrombin Inhibitors

• Leech proteins
• Natural FDA-approved indication
• Hirudin IV/SQ -
• Bivalirudin IV PTCA
• Lepirudin IV/SQ HIT
• Synthetic
• Argatroban IV HIT
• Ximelagatran PO -

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Ximelagatran (ExantaR) - AstraZenica

• Direct thrombin inhibitor -- quicker action
• Orally absorbed
• Converted to active drug -- melagatran
• Mainly cleared by kidney low protein binding
• No known drug intxs
• Does not require monitoring
• Minimal bleeding
• Minimal side effects? -- transaminitis
• Expense??

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Schulman S THRIVE III. Secondary prevention of
venous thromboembolism with the oral direct
thrombin inhibitor ximelagatran. NEJM Oct. 30,
30033491713

• Multicenter (18 countries, outside U.S.) RDBPCT
• Ximelagatran for secondary prevention of VT
  (DVT/PE)
• Pts with a VT, s/p 6 months usual anticoagulant
  therapy
• Then randomized to ximelagatran or placebo x 18
  months
• Primary outcome symptomatic recurrent VT
• Secondary outcomes adverse events (death,
  bleeding)

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Methods Design

• 1356 pt originally enrolled ? 1233 pts
• Inclusion criteria
• 18 yo
• Symptomatic DVT/PE
• UTZ, V/Q, venogram, spiral CT, Angio
• Treated for 6 months with oral anticoagulant
• Exclusion criteria
• Need for continued anticoagulation
• High risk of bleeding
• Hg
• pregnant/lactating, liver disease, life
  expectancy
• Permitted
• ASA

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Methods Design

• 1233 pts with acute DVT/PE
• Treated for 6 months with oral anticoagulant per
  primary physicians
• Randomized to
• Ximelagatran 24mg BID (n612)
• Placebo BID (n611)
• First dose given w/in 7 days of stopping oral
  anticoagulant
• Treated for mean of 18 months
• No coagulation monitoring

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Group characteristics

• Baseline characteristics similar
• Compliance similar in both groups
• Use of ASA (7 9) and NSAIDS (16 17) similar
  in both groups

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Results

• placebo ximelag P value
• Recurrent VT 71 (12.6) 12 (2.8)
  
• Bleeding 111 134 0.17
• Maj. Hem 5 6
• Death 7 (3 PE) 6 (0VT)
• ALT3xULN 1 6
  
• Mostly in 1st 4 months, decreased spontaneously
  w/ or w/o D/C drug

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Authors conclusion

• Long-term treatment with ximelagatran, without
  monitoring of coagulation or adjustments of the
  dose, offers a clinically meaningful reduction in
  the incidence of recurrent VT

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Study Limitations

• Supported (authored) by AstraZeneca
• Not U.S. patients

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Perspective

• Previous studies with ximelagatron
• TKR/THR (2002-2003 studies)
• 36mg bid ximelagatran warfarin
• Ximelagatran 24mg bid enoxapirin 40mg qd
• Ximelagatran 24 mg bid

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Other ximelagatran studies...

• VT or A. Fib (2003 studies)
• THRIVE - acute VT x 6 mo (n2491)
• Ximelagatran 36mg bid warfarin (2 vs. 2.1)
• SPORTIF III - A. Fib x 17 mo (n3407), open
• Ximelagatran 36mg bid warfarin (1.6 vs. 2.3)
• ESTEEM - Recent MI x 6 mo (n1883)
• Ximelagatran 24-66mg/ASA 160mg ASA 160mg
• But more bleeding in ximelagatran/ASA group

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My Bottom Line

• Ximelagatran is a promising new drug with many
  characteristics of the ideal oral anticoagulant
• Important issues pending
• Confirmation of efficacy and safety

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Case

• Mr. T is on warfarin with a difficult to control
  INR and trouble keeping frequent clinic
  appointments
• Are the direct thrombin inhibitors as effective
  as warfarin, and can they be used without
  coagulation monitoring
• Large initial studies suggest this to be true,
  though side effects (transaminitis) and drug
  costs need better characterization
• Ximelagatran is currently pending FDA
  review/approval (2004?)

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Case 2

• In clinic today, you see Mr. J, a 39 yo M with
  multiple sclerosis
• He requests a letter stating that he has a
  medical need for marijuana, because it helps
  reduce spasticity from MS
• You ask your attending if there is data that
  marijuana helps spasticity in MS, and what are
  the legal ramifications of recommending marijuana?

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Background MS

• MS symptoms
• Muscle spasticity and spasms - 90 of pts
• Pain, reduced mobility, interference with ADLs
• Bladder sxs - 90
• Ataxia and tremor - 80
• Sensory sxs, including pain - 50
• Anecdotally, marijuana and cannabinoids have been
  suggested to help MS related pain, bladder sxs,
  tremor and spasticity

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Background marijuana

• Marijuana (Cannabis sativa)
• Herbal drug made illegal in mid-1930s
• Delta-9-THC isolated in 1960s
• Synthetic oral THC Dronabinol Marinol(R)
• Anti-emetic for chemo
• Anorexia from AIDS
• 3-14/capsule
• Many pts grow or buy marijuana

• Proposed indications
• Anti-emetic
• Anti-spasticity
• Analgesic
• Appetite stimulatant
• Anti-glaucoma
• Anticonvulsant
• Anti-asthmatic
• Sedative-hypnotic

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Zajicek et al (UK MS Research Group).
Cannabinoids for treatment of spasticity and
other symptoms related to multiple sclerosis.
Lancet Nov 8, 20033621517

• To test the notion that cannabinoids have a
  beneficial effect on spasticity and other sxs
  related to MS
• Multicenter RDBPCT
• 15 week study with 8 office visits
• Recruited from 33 Neurology Rehab centers in
  the UK

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Methods Design

• 18-64 yo with stable MS for 6 months who have
  problematic spasticity
• Ashworth score 2 (out of 5), in two or more LE
  muscle groups
• Ashworth score measures limb catching, muscle
  tone or rigidity, and ROM on a 5 pt scale
• Assessed by a physiotherapist or MD
• Excluded patients with other medical problems
• Any major illness, infection, cognitive
  impairment, pregnant, fixed tendon contractions,
  h/o THC use, taking beta-interferon

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Methods Design

• 657 randomized pts -- 630 ITT -- 611 analyzed
  for primary outcome
• Randomly assigned to
• Canabis extract (2.5mg D9-THC 1.25mg
  cannabidiol)
• Synthetic D9-THC Dranabinol (Marinol) 2.5mg
• Placebo
• Extract-placebo
• THC-placebo
• Dose based on body wt, 2-5 capsules BID
• Start with a 5 week titration phase, increasing
  weekly

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Outcome Measurements

• Primary
• Change in spasticity using the Ashworth score
• Secondary
• Mobility
• Timed 10 meter walk Rivermead Mobility Index
• Disability
• Barthel Index UK Neurological Disability Score
  (UKNDS)
• General well-being or distress
• GHQ-30
• 9 category rating scales
• Spasticity, tremor, stiffness, pain, depression,
  sleep, fatigue
• 4 questions by the physician about overall effect
  on
• Spasticity, tremor, pain, bladder function

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Results

• Primary measurement
• Ashworth scale treatment groups placebo
  (P0.29)
• Secondary measurements
• Walk times D9THC Extract Placebo
• Decrease by 12 4 4
• Category rating scales
• Tx placebo spasticity, spasms, pain, sleep
  quality
• Tx placebo tremor, irritability, depression,
  tiredness, energy
• Physician specific questions
• Tx placebo spasticity, pain
• Tx placebo tremor, bladder sxs
• Rivermead mobility index, Barthel UKNDS
  disability scores, GHQ-30 tx placebo

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Adverse Effects

• Serious adverse effects
• Similar in number across all groups (slightly
  more in placebo group)
• Minor adverse effects
• Tx groups with more
• dizziness/lightheadedness, dry mouth, diarrhea

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Blinding Assessment

• Asked pts and study personnel which tx they
  thought the pt had received
• Patient
• 77 of in active tx groups guessed they were
  taking active med
• 50 in placebo group thought they were taking
  active med
• Study personnel
• Doctors correlated with patient guess
• Assessor of Ashworth score (mainly
  physiotherapist) could not guess correctly

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Authors conclusion

• Cannabinoid tx did not improve spasticity
  associated with MS (as measured by the Ashworth
  scale)
• Some benefit in secondary outcome measures were
  seen, particularly in assessing mobility and the
  patients perceptions of the effects of
  spasticity, thereby improving subjective symptoms

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Study Limitations

• Well done study
• Degree of unmasking in active tx groups

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Perspective

• Similar results in 4 small RDBPCTs
• Largest study 16 pts
• Subjective symptomatic improvements, but no
  objective evidence for efficacy

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My Conclusion

• Oral THC is unlikely to reduce spasms from MS
• THC may alter the perception of spasm or pain
  which may provide benefits in some MS pts
• Blinding problems hinder interpretation
• smoking marijuana ?? oral THC

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Perspective Legal issues

• Active medical marijuana legalization movement
• California medical marijuana initiative (Prop
  215), 1996
• Gave Californians the right to possess and
  cultivate (not buy or sell) marijuana for medical
  purposes deemed appropriate and recommended by a
  physician (orally or in writing)
• Federal govt. responded by threatening physicians
  who recommend its use with investigation and loss
  of prescription privileges under federal DEA
  regulation
• Federal govt. also prosecuted growers and sellers
  under federal laws that superceded state laws

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Legal issues, cont...

• U.S. Supreme court (Oct. 2003)
• Doctors in California (and 8 other states with
  medical marijuana laws) do not risk federal
  investigation or punishment if they choose to
  recommend the use of marijuana by their patients
• U.S. 9th Circuit Court of Appeals (Dec. 16, 2003)
• Federal govt. cannot prosecute patients who use
  medical marijuana as long as they cultivate their
  own cannabis or obtain it for free (and dont
  transport across state lines)
• Federal govt. will most likely appeal -- U.S.
  Supreme Court

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Case

• Mr. J is requesting a letter stating that he has
  a medical need for marijuana for spasticity from
  MS
• Does marijuana helps spasticity in MS?
• Probably will not help objectively, but may have
  some subjective benefits
• Can you provide him with a letter recommending
  marijuana?
• Yes, under 1996 California initiative (Prop 215),
  medical use of marijuana is legal in this state
• Oct. 2003 U.S. Supreme Court action, you are
  protected from federal prosecution
• Remind the patient it is still illegal to buy or
  sell marijuana he must grow his own or somehow
  obtain it for free

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Pharmaceutical Update

• Dec. 2003

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New Antibiotics

• Gemifloxacin mesylate (Factive(R))
• Broad spectrum flouroquinolone
• Excellent activity against S. pneumoniae
• 320mg PO daily
• AECB, CAP
• Daptomycin (Cubicin(R))
• 1st in a new class of antibiotics, the cyclic
  lipopeptides
• Injection
• Gram positive (including MRSA, not VRE)
• Soft tissue infections (abscess, wound, ulcer)

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Viagra, move over...

• PDE5 inhibitors sildenafil, vardenafil,
  tadalafil
• 65-80 efficacy
• SE HA, flushing, dyspepsia
• C/I nitrates, alpha-blockers
• Sildenafil (Viagra(R)) - 1998 (25/50/100mg)
• 4 hr duration
• decrease absorption with fatty meal
• Vardenafil (Levitra(R)) - 2003 (2.5/5/10/20mg)
• Similar to sildenafil (slightly longer T1/2 and ?
  quicker onset)
• Tadalafil (Cialis(R)) - 2003 (5/10/20mg)
• 36 hr duration
• No interaction with food

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JCAHO Abbreviation Requirements

• U - un - units
• q.o.d. - every other day
• q.d. - q day - once daily
• q.i.d. - 4 times a day
• ug - µg - mcg
• MS - MSO4 -- morphine
• Mg - MgSO4-- magnesium
• 5 mg - 5.0 mg 0.5 mg - .5mg
• Order forms - all chart documents (including
  notes)
• OVMC - all Public hospitals - all U.S. hospitals
• 100 compliance by 1/1/04 - 1/1/05 - 1/1/06

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To download this lecture

• www.uclaSFVP.org/lectures.htm