Journal Update August 2003

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Journal UpdateAugust 2003

• Michael Rotblatt, MD
• Soma Wali, MD

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Journal Update - Introduction

• Review 3-4 articles/month
• NEJM, Annals of Internal Medicine, JAMA
• High-quality RCTs, SRs/MAs
• with important results that may change our usual
  therapies
• other articles of interest, particularly to
  general internists

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Articles Today

• Tx of Menopausal symptoms
• Utility of an herbal therapy
• Utility of an SSRI
• Anticoagulation
• Secondary prevention of DVT in cancer patients
  using warfarin vs. LMWH
• Pharmaceutical Update

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Case One

• A 52 year old post-menopausal woman presents to
  your office c/o 8-12 hot flashes/day
• She had been using HRT which helped relieve her
  symptoms.but after she heard the news last year
  of serious side effects with estrogen HRT, she
  stopped, and her symptoms worsened
• She asks you if there are any non-hormonal
  alternatives (especially herbal medicines) that
  are effective to relieve hot flashes

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Background on HRT

• Previous indications for using HRT
• Tx of peri-menopausal sxs (hot flashes, etc.)
• Osteoporosis prevention
• CAD prevention
• Prevention of dementia/Alzheimers disease??
• For patients with or without a uterus
• without uterus --- estrogen alone
• with uterus --- estrogen progesterone

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Womens Health Initiative - JAMA 2002288321

• Large prospective RCT evaluating HRT in 16,000
  postmenopausal women (50-79 y.o.), average f/u
  5.2 yrs
• Benefits
• Reduced risk of hip fracture (5/10,000
  person-yrs)
• Reduced risk of colorectal cancer (6/10,000
  person-yrs)
• Decreased hot flashes in younger women with sxs
• Risks
• Increased CV disease
• CHD events (7/10,000 person-yrs)
• Strokes (8/10,000 person-yrs)
• PE (8/10,000 person-yrs)
• Increased invasive breast CA (8/10,000
  person-yrs)
• Increased risk dementia/cognitive impairment
  (23/10,000 p-y)

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Background Estrogen alternatives

• Herbs supplements
• Problem Lack of high-quality RCTs
• Examples Isoflavone-containing phytoestrogens
  (soy, red clover), black cohosh, dong quai, Vit
  E...
• Drugs
• Problem small RCTs, mainly with breast cancer
  pts
• Examples
• Antidepressants
• SSRI Paroxetine (Paxil), Fluoxetine (Prozac)
• SNRI Venlafaxine (Effexor)
• Clonidine
• Gabapentin (Neurontin)

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Tice et al. Phytoestrogen Supplements for the
Treatment of Hot Flashes The Isoflavone Clover
Extract Study.JAMA July 9, 2003 290207

• Randomized, double-blind, placebo-controlled
  trial of post-menopausal women in the U.S.
• Objectives
• To compare the efficacy and safety of 2 red
  clover isoflavone dietary supplements (from same
  mfgr) in symptomatic post-menopausal women
• Primary objective frequency of hot flashes
• Secondary objective QOL and adverse events

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Method/Design

• 252 post-menopausal women, 45-60 y.o., with at
  least 35 hot flashes per week
• Exlusions
• vegetarians
• consumed soy (isoflavone) products
• took medications with hormonal properties or that
  affect isoflavone absorption
• significant GI disease
• Supplements independently analyzed and verified
  for isoflavone content

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Intervention

• After a 2 week placebo run in, randomly assigned
  to one of 3 groups
• Placebo
• Promensil(R) (82 mg/dy of total isoflavones)
• Rimostil(R) (57 mg/dy of total isoflavones)
• Followed for 12 weeks
• Women recorded hot flashes in a daily diary
• Validated menopausal QOL scale also used
• Of 252 patients, 246 (98) completed the study

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Results

• No statistically significant changes were found
  on reduction of daily hot flashes
• Placebo Promensil Rimostil
• Baseline 7.8 8.5 8.1
• 12 wks 5.0 5.1
  5.4
• (36) (41) (34)
• Quality of life improvements and adverse events
  were similar in the 3 groups

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Study Limitations

• Most pts were post-menopausal
• Peri-menopausal pts may be more symptomatic
• But required 35 hot flashes/week fairly
  symptomatic

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Authors Conclusion (and our Bottom Line)

• These Red Clover isoflavone supplements
  (Promensil and Rimostil) have no clinically
  significant effects on hot flashes or other
  symptoms of menopause
• For all studies of Dietary Supplements
• Cannot extrapolate results to different products
  or doses

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Perspective Herbs for Menopause

• Isoflavone-containing phytoestrogens
• Soy -- mixed results in 10 RCTs, not impressive
• Red clover -- 2 other - DBRCTs, 1 poor-quality
  
• Black cohosh
• older European studies poor quality
• One U.S. high quality study in breast Ca pts -
• Others
• dong quai -- one high quality study -
• Asian ginseng -- one high quality study -

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Case

• 52 year old postmenopausal woman with severe hot
  flashes interested in non-HRT alternatives
• Is this patient like those in the study?
• Currently no good evidence that herbal
  alternatives work, but if you want to try them
  please give me feedback on how they work for you
  (remember the placebo effect)
• She asks you, are there any drugs that work?

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Stearns et al. Paroxetine Controlled Release in
the Treatment of Menopausal Hot Flashes. JAMA
June 4, 2003 2892827

• Multicenter (17 U.S. sites) randomized, double
  blind, placebo controlled, parallel group study
• Primary outcome
• Mean change from baseline to week 6 in the daily
  hot flash composite score (frequency x
  severity)
• Secondary outcomes
• Difference between two dosages (12.5 mg vs. 25
  mg) of Paroxetine CR
• Safety and tolerability

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Methods/Design

• 225 women screened -- 165 enrolled
• Postmenopausal women with at least 2-3 hot
  flashes/day or 14 bothersome flashes per week
• Exclusions
• Active psychiatric disorders (including
  depression and anxiety) or psych medications
• Intolerance to SSRIs
• Cancer
• Substance dependence
• HRT within 6 weeks of study

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Methods/Design

• Daily hot flash diaries
• Previously validated
• Daily hot flash composite score
• frequency x severity rating (1 mild --- 4
  severe)
• Menopausal QOL and other scales used

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Intervention

• Initial 1 week single-blind placebo run in phase
• 165 women randomized to one of 3 groups
• Placebo
• 12.5 mg/day paroxetine CR
• 25 mg/day paroxetine CR
• Followed for 6 weeks
• study visits at 1, 3, and 6 weeks

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Results

• Both paroxetine treatment groups showed a
  significant benefit over placebo after 6 weeks
• Placebo 12.5mg 25mg
• Baseline composite 14.2 16.5 13.6
• 6 wks 10.2 8.1 6.4
• (37.8)
  (62.2) (64.6)
• Baseline HF frequency 6.6 7.1 6.4
• At 6 wks 4.8 3.8 3.2

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Side Effects

• Reported SEs generally mild-moderate
• HA, dizziness, nausea
• 53.6 in placebo group
• 58.3 in Paroxetine groups
• 12.5 mg/dy 20 possibly/probably related to med
• 25 mg/dy 31 possibly/probably related to med

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Authors Conclusion

• Paroxetine CR may be an effective and acceptable
  option in treating hot flashes in menopausal
  patients

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Study Limitations

• Low proportions of black and Asian women in the
  study
• Black women experience more hot flashes, and
  Asian women less
• Short duration of therapy (only 6 wks)
• Disproportionate of women discontinued study
  meds due to adverse effects
• 2 placebo
• 12 paroxetine CR

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Bottom Line

• Paroxetine CR appears beneficial for tx of hot
  flashes
• Low dose (12.5 mg) may be as effective as higher
  dose (25mg), with less side effects
• Several issues remain
• Duration of benefit?
• CR product vs. immediate-release products?
• Different effects with different SSRIs?

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Perspective Non-hormonal drugs for HRT

• Drugs found effective in small RCTs
• Antidepressants (studies in breast cancer pts)
• Paroxetine (10-20 mg/dy) - 1 study
• Fluoxetine (Prozac) 20 mg/dy - 1 study
• Venlafaxine (Effexor) 37.5-75 mg/dy - 1 study
• Clonidine oral/patches - several studies
  (modest benefits)
• Gabapentin (Neurontin) 1200 mg/dy - 1 study

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Case

• 52 year old post-menopausal woman complaining of
  severe hot flashes
• Is this patient like those in the study?
• Trial of paroxetine appears reasonable
• CR vs. regular release?
• try low-dose first
• Other evidence-based medication options
• fluoxetine, venlafaxine, clonidine, gabapentin

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Case 2

• 72 yo F with stage III colon CA is being treated
  with chemotherapy
• Admitted with a proximal LE DVT and
  anticoagulated initially with heparin
• Your Attending asks you,
• For long-term prevention of VT recurrence in
  this patient, which is better warfarin or LMWH?

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Background

• Patients with CA
• have a higher risk of recurrent VT (PE/DVT)
• many problems with warfarin
• Higher major bleeding rate (13/yr)
• Thrombocytopenia, drug intx, malnourished, liver
  dysfxn
• Interruptions for invasive procedures
• Frequent monitoring
• LMWHs are effective anticoagulants that obviate
  some of the problems seen with warfarin

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Lee et al. LMWH vs. a Coumarin for the
Prevention of Recurrent Venous Thromboembolism in
patients with Cancer. NEJM July 10, 2003349146

• Multicenter (8 countries), open RCT x 6 months
• 676 adults with active CA and new VT
• 465 DVT alone, 211 PE /- DVT
• 90 solid tumors, 67 with mets
• Exclusions
• C/I to anticoag, Cr 3 x nl, pregnant

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Methods/design

• 676 pts randomized (338 in each group) to
• Dalteparin (200 IU/kg qd x 1 mo, then 80 x 5 mo)
• Warfarin/Acenecoumarol (initial Dalteparin x 5-7
  dys) with goal INR 2-3
• F/U x 6 months
• Contacted by phone q 2 wks
• Clinic visits at 1 wk and 1, 3, and 6 months
• Similar baseline characteristics
• Age, outpt/inpt, mets, chemo tx, cigs, h/o VT,
  transient RFs

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Results

• Primary outcome 1st episode symptomatic VT
• Dalteparin Oral
  Anticoag
• Total VT 27 (9) 53 (17) p0.002
• DVT 14 37
• PE (total) 13 16
• PE (fatal) 5 7

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Results

• Secondary outcome bleeding, death
• Dalteparin Oral Anticoag
• Major Bleed 6 4 n.s.
• Any Bleeding 14 19 n.s.
• Death 39 41 n.s.
• Major bleeding death, critical site, txf 2
  un, dec. Hg 2
• 90 of deaths due to progressive CA

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Authors Conclusion

• Dalteparin is better than oral anticoagulation to
  prevent recurrent symptomatic VT in patients with
  active CA

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Study Limitations

• Non-blinded
• Sponsored by Pharmacia
• Patients in oral anticoagulation group were in
  therapeutic range (INR 2-3) 46 of time
• 30 of time
• 20/53 (38) recurrent VTs
• 24 of time 3
• 6/12 major bleeds

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Perspective

• Previous studies comparing LMWH to warfarin in CA
  pts
• found no difference, but small studies
• Major bleeding rate higher for warfarin
• 16 warfarin (over 3 months)
• 7 LMWH
• Dalteparin (Fragmin) other LMWHs??
• Enoxaparin (Lovenox)
• Tinzaparin (Innohep)

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Bottom Line

• Dalteparin appears to be better than warfarin to
  prevent recurrent VTs in pts with active CA
• Limitations of study prevent firm conclusion?
• Unclear if other LMWHs dalteparin
• Other criteria for choosing warfarin vs. LMWH
• Cost (LMWH expensive)
• Practical issues
• LMWH - daily SQ injections
• Warfarin - monitoring, drug intx, malnutrition,
  liver dis., low plts, invasive procedures, etc

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Case

• 72 yo F with active CA and a proximal LE DVT
• For long-term prevention of recurrence, which is
  better warfarin or LMWH?
• Is our patient like those in the study?
• LMWH (Dalteparin) may be better
• Practical issues may be just as valid

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Pharmaceutical Update

• New drugs and pharmaceutical news of interest to
  internists

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FluMist(R)

• First flu vaccine nasal spray
• 85 effective in preventing influenza A B
• For healthy people aged 5-49
• Not approved for high-risk patients (elderly,
  chronic diseases) due to inadequate data
• Attenuated live virus vaccine
• C/I in immunosuppressed pts
• SE nasal congestion/rhinorrhea, HA, sore
  throat, cough
• Cost 46 (2-3 x more than injection)

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Omalizumab (Xolair(R))

• 1st biologic tx for mod-severe persistent asthma
• IgG monoclonal Ab
• Inhibits IgE Ab binding to receptors on mast
  cells/basophils
• For allergic asthma in patients 12 y.o. when
  inhaled steroids arent sufficient
• Administered SQ every 2-4 weeks
• Cost 10,000/ year

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Prilosec OTC(R)

• The first PPI to be sold OTC
• For pts with frequent heartburn ( 2 dys/wk)
• Dose 20 mg ( Rx dose)
• Cost
• Onset of activity days
• H2-blocker hour

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New Drugs for Cholesterol

• Ezetimibe (Zetia(R))
• Selective cholesterol-absorption inhibitor -
  works at the brush border of gut wall (intestinal
  villi)
• Cholestyramine/colestipol (BAS) - binds bile
  acids
• Plant stanols/sterols - prevent cholesterol
  incorporation into fat micelles
• No effects on other sterols or lipid-soluble
  vitamins
• Decreases LDL by 15-20 ( decr TG, incr HDL)
• Dose 10 mg QD
• Used alone, or in addition to statins
• Taken with or without food
• SEs placebo (poorly absorbed)
• angioedema

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New drugs for cholesterol...

• Rosuvastatin (Crestor (R))
• Potent statin
• 10 mg 20 mg atorvastatin 80 mg simvastatin
• Dose 10 - 40 mg/day
• Adverse effects
• Only statin associated with proteinuria
• FDA did not approve 80 mg dose due to 7 cases of
  rhabdomyolysis
• Pravigard PAC(R)
• Pravastatin (20, 40, 80 mg) ASA (81, 325 mg)
• Separate tablets initially --- single tablet

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Shotgun pill for CV disease? - 6/28 BMJ

• Polypill a statin, thiazide, beta-blocker,
  folic acid, and aspirin
• Potential to lower CV disease by 80 if taken by
  everyone 55 y.o.
• 1/3 of those 55 y.o. would live 11 more years
  free of MI or stroke
• Improve compliance, less expensive?
• Negatives
• pts with low BP, dosage adjustments, side effect
  to one ingredient...

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