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Journal Update August 2003

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... menopausal woman presents to your office c/o 8-12 hot flashes/day ... Postmenopausal women with at least 2-3 hot flashes/day or 14 bothersome flashes per week ... – PowerPoint PPT presentation

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Title: Journal Update August 2003


1
Journal UpdateAugust 2003
  • Michael Rotblatt, MD
  • Soma Wali, MD

2
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

3
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

4
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

5
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

6
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)

7
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)

8
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

9
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

10
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

11
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

12
Study Limitations
  • Most pts were post-menopausal
  • Peri-menopausal pts may be more symptomatic
  • But required 35 hot flashes/week fairly
    symptomatic

13
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

14
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 -

15
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?

16
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

17
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

18
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

19
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

20
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

21
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

22
Authors Conclusion
  • Paroxetine CR may be an effective and acceptable
    option in treating hot flashes in menopausal
    patients

23
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

24
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?

25
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

26
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

27
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?

28
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

29
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

30
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

31
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

32
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

33
Authors Conclusion
  • Dalteparin is better than oral anticoagulation to
    prevent recurrent symptomatic VT in patients with
    active CA

34
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

35
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)

36
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

37
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

38
Pharmaceutical Update
  • New drugs and pharmaceutical news of interest to
    internists

39
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)

40
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

41
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

42
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

43
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

44
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...

45
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