Journal Update July 2003

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Journal UpdateJuly 2003

• Soma Wali, MD
• Michael Rotblatt, MD
• UCLA-SFV and GLAVA
• Internal Medicine Residency Programs

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Introduction

• Purpose
• Busy schedules/little time to read new journals
• Update housestaff and faculty on recent
  literature
• Methods
• Review last 1-2 months of
• NEJM, Annals of Internal Medicine, JAMA
• ACP Journal Club, Journal Watch
• Select 4 articles/month

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Intro, cont...

• Selection Criteria
• 1. Studies with important results that may
  change our usual therapies
• High-quality DBRCTs
• Systematic reviews, meta-analyses, impt.
  concensus
• 2. Other articles of interest, particularly to
  general internists
• Different than Journal Club (in addition to)

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Articles Today

• Dietary approaches for weight loss, including an
  evaluation of the Atkins Diet
• Warfarin for prevention of recurrent venous
  thromboembolism
• Review of the SPAF (Stroke Prevention in Atrial
  Fibrillation) Trials

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Case 1

• 38 y.o. morbidly obese F (300 lbs) with h/o DM,
  HTN, hyperlipidemia
• Presents to your clinic c/o pain in knees,
  fatigue and depression
• Pt understands that all her problems relate to
  her weight
• She asks which diet is best for wt loss
  low-carbohydrate or low-fat?

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Background Weight loss

• At any time, 45 of women and 30 of men in the
  U.S. are trying to lose weight
• Despite these efforts, the prevalence of obesity
  has doubled in last 20 years
• of obese male and females doubled from 91 to
  1998
• of states with more than 15 of people with
  obesity increased from 8 to 79
• Prevalence of obesity in U.S increased from 17.9
  (1998) to 19.8(2000)

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Background Diets

• Low fat, high carb, energy deficit diet
• (eg, traditional AHA-type diet)
• Low fat, low carb
• (eg, Weight Watchers-type, calorie count)
• High fat, high protein, low carb
• (eg, Atkins)

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Samaha, et al. A low-carb as compared with a
low-fat diet in severe obesity. NEJM May 22,
20033482074

• Primary outcome
• 10 wt loss at 6 months
• Wt measured monthly
• Secondary outcomes
• Glucose and insulin sensitivity (calculated)
• Lipids and BP

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Study methods/protocol

• 132 severely obese pts
• BMI 43 (morbid obesity)
• 39 DM, 43 metabolic syndrome
• Randomly assigned to
• Low fat diet (n68)
• Low carb diet (n64)
• Matched for baseline characteristics
• BMI, wt, age, race, gender, DM, lipids, CAD,
  depression, cigs...

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Study methods/protocol

• All pts attended group teaching sessions
• Weekly meetings x 4 weeks, then monthly
• Teaching sessions consisted of
• Diet overview handouts
• Instruction on nutritional labels
• Sample menus and recipes
• Book on counting calories
• No specific exercise program recommended
• Dietary compliance measured by 24 hr intake
  diaries

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Study methods

• Low-carb group
• Restrict carbs to
• No restriction on fat
• Asked to consume vegies/fruits with high fiber
  (high fiber/carb ratio)
• Low-fat group (AHA)
• Caloric restriction to 500 calorie deficit/day

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Results

• Primary outcome (achieving 10 wt loss)
• Low-carb group low-fat group (AHA) (p0.002)
• 9/64 (14) in low-carb group
• 2/64 (3) in low-fat group
• Low-carb group decreased wt compared to baseline
  (p0.02)

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Results

• Secondary outcomes
• Serum lipids
• decreased TGs in low-carb group (p0.001)
• no change in TC, LDL, HDL in either group
• Glycemic control
• diabetics
• mean FBG in diabetics decreased more in low-carb
  group compared with other group (p0.02)
• HgA1c decreased in both groups similarly
• non-diabetics
• insulin sensitivity increased in low-carb group
• BP no significant overall or between-group
  changes

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Study Conclusion

• Severely obese patients with high prevalence of
  DM and metabolic syndrome lost more weight in a 6
  month period on a low-carb diet than a low-fat
  diet
• Low-carb diet
• benefits TGs, glycemic control in diabetics,
  insulin-sensitivity in non-diabetics
• No adverse effects on other serum lipids

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Study Limitations

• 6 month duration
• Small sample size
• Significant early drop-out rate
• Few patients in either group achieved primary
  goal of 10 weight loss
• Morbidly obese pts (BMI 43)

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Bottom Line

• Low-carb diet (Weight Watcher/calorie count) is
  at least as effective as the low-fat/calorie
  restricted diet (traditional AHA) in morbidly
  obese pts (BMI 43)
• Low-carb diet may be more effective for wt loss,
  and have benefits for TGs and diabetes, but
  limitations of this study reduced our certainty

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Case

• 38 y.o. morbidly obese F with DM, HTN,
  hyperlipidemia, knee pain, fatigue and depression
  asking for your diet recommendation
• Is our pt like those in the study?
• You can tell her that she may benefit more from
  low-carb diet than low-fat diet
• However, the most effective diet is probably the
  one that she can best adhere to in the long run,
  along with an exercise regimen

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Case 2

• Your 45 y.o. obese neighbor asks you, I just
  started the Atkins diet. Since youre a
  doctor,whats your opinion of it?
• You ask him about his hx, which includes HTN,
  hyperlipidemia, DM and CRI
• Youre concerned that the Atkins diet might be
  detrimental for him, considering these medical
  problems

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Background Atkins Diet

• Despite popularity of this low-carb/high-fat/high-
  protein diet, no RCTs have been published
• Originally described in 1973 in a book by Dr.
  Atkins, revised in 1992, again in 2002
• 10 million copies sold in the U.S.
• The medical establishment has been particularly
  concerned about the effects on lipids, ketones
  (diabetes), renal function, etc.

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Foster, et al. A randomized trial of a low-carb
diet for obesity. NEJM May 22, 20033482082

• Primary outcome
• Wt loss
• Secondary outcome
• Lipids, BP, insulin response to OGTT, urine
  ketones

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Study methods/protocol

• 1 yr multicenter RCT
• 63 overweight patients (average BMI about 33)
• Randomized to
• High-carb/low-fat (AHA-type) n30
• Low-carb/high-fat/high-protein (Atkins) n33
• Exclusions
• DM, lipid lowering meds, wt loss meds
• At 0, 3, 6, and 12 months
• All subjects met individually with dietician for
  15-30 min., and had labs drawn

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Study methods/protocol

• Low-carb diet group -- typical Atkins diet
• Received a copy of the Atkins diet book to read
  and follow
• 1st 2 weeks - 20 g/dy carbs, then minimal carbs
  thereafter
• no restriction on fat or protein
• Conventional diet group
• Recommended high carb/low fat diet
• 60 carbs, 25 fat, 15 protein
• Calorie restriction
• 1200-1500 Kcal/dy for women
• 1500-1800 Kcal/dy for men
• Received instruction on calorie counting and a
  book

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Results

• Wt loss
• Atkins diet was significantly better at 3 and 6
  months, not at 12 months
• 3 months 6 vs. 2 wt loss (p0.001)
• 6 months 6.5 vs. 2.5 (p0.02)
• 12 months 3 vs. 2 (not stat
  sign)
• Lipids - compared to baseline
• Atkins diet
• decrease in TGs and increase in HDL at all time
  points
• no changes in TC or LDL
• Conventional diet
• decrease in TC and LDL at 3 months only

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Results, cont

• Urinary ketones
• Atkins diet more ketones at 3 months, but
  not thereafter
• No relationship between wt loss and urinary
  ketosis
• OGTT and insulin sensitivity
• No significant differences between groups
• BP
• No significant differences between groups

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Study Conclusion

• Atkins diet
• Greater wt loss (absolute diff about 4) vs.
  traditional low-fat/high-carb diet for up to 6
  months
• Difference was not significant at one year
• Not detrimental regarding urinary ketones,
  lipids, BP, glucose, insulin-sensitivity
• In fact, may be beneficial to pts with CRFs such
  as high TGs or low HDL

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Study Limitations

• Small sample size
• 1 yr duration
• Relatively healthy patients
• no diabetics or hyperlipidemic patients on meds

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Bottom Line

• Atkins diet is at least as effective as
  traditional AHA-type diet based on one RCT
• Initially, wt loss appears to be more (1st 6
  months)
• No detrimental effects on lipids or glucose
• However, long-term effects of this diet are
  unknown, and study did not include pts with
  diabetes, hyperlipidia, CRI, etc.
• This study is very suggestive of the benefits of
  the Atkins diet, but needs verification

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Case

• 45 y.o. obese M with HTN, hyperlipidemia, DM and
  CRI asking about the Atkins diet
• Is our patient like those in the study?
• Might be reasonable to try the Atkins diet, but
  this study does not answer all our concerns
• If used, have your doctor monitor diseases
  carefully
• Recommend exercise in addition to diet
• Caution about long-term use
• Consider switching to a more well-balanced diet
  after initial wt loss?

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Case 3

• 66 y.o. M diagnosed with right calf DVT is seen
  in your clinic after 6 months of warfarin tx
• No identifiable risk factors for DVT
• He asks you how long do I need to stay on
  Coumadin?

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Background Anticoag for DVT

• Usual tx for 1st DVT 3-12 mo. of warfarin (INR
  2-3)
• Surgery/trauma - 3 months
• Idiopathic - 6 months
• Recurrent/Hypercoag states - 12 months - life
• After warfarin cessation, DVT recurrence
  6-9/year
• Chronic warfarin can almost completely prevent
  recurrence
• Long-term warfarin -- major bleeding rate
• 5-9/yr in observational studies (2-4/yr in
  clinical trials)

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Ridker, et al. Long-term, low intensity warfarin
therapy for the prevention of recurrent venous
thromboembolism. NEJM April 10, 20033481425-34

• PREVENT Trial
• RDBPCT, age 30, f/u 4 yrs
• 750 pts -- 508 pts
• idiopathic VT (DVT/PE)
• Exclusions trauma/surgery, met. CA, LA/APL Abs,
  major GIB/hemorrhagic CVA/drugs affecting
  clotting
• All pts treated initially for 3 months (median
  6.5 months) with full dose warfarin (INR 2-3)

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PREVENT Trial, cont...

• 508 pts randomized to low intensity warfarin (INR
  1.5 - 2.0) or placebo
• Followed q 2 months for dose adjustments (placebo
  sham dose changes)
• Results
• Mean duration f/u 2.1 yrs (max. 4.3 yrs)
• Warfarin median INR 1.7 median dose 4 mg

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(No Transcript)
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Study Conclusion

• After 6 months usual dosing, long term
  low-intensity warfarin (INR 1.5-2.0) is an
  effective and safe method to prevent recurrent
  idiopathic VT

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Study Limitations

• Good study
• Idiopathic VT (mainly DVTs?)
• Other hypercoagulable states?
• Similar risk reductions with or without Factor V
  Leiden or G20210A prothrombin mutations

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Perspective

• Other studies
• Low-dose warfarin effective for primary
  prevention
• decreased 1st VT in women with metastatic breast
  CA
• decreased 1st VT in pts with indwelling catheters
• Usual dose vs. low-dose warfarin to prevent
  recurrence?
• Blood 2002 abstract - usual dose warfarin more
  effective than low-dose (INR 1.5-1.9) to prevent
  recurrence (w/o significant bleeding increase)
• Ximelagatran (oral direct thrombin inhibitor)

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Bottom Line

• Low-intensity warfarin (INR 1.5-2.0) should be
  considered for patients with idiopathic VT (DVT)
  after 6 months usual tx
• Duration 2-4 yrs vs. life-long??
• Need to take into account individual patient
  characteristics
• Monitoring, cost, f/u and compliance, drug intx,
  patient preference...

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Case

• 66 y.o. M with idiopathic DVT treated with
  warfarin for 6 months
• Is our patient like those in the study?
• Chronic low-dose warfarin should be considered
  and discussed
• Otherwise, warfarin can be discontinued

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Case 4

• 78 y.o. F with recently diagnosed A. Fib., rate
  controlled on diltiazem and digoxin
• PMH knee OA and bladder incontinence
• You would like to start warfarin for stroke
  prevention
• The patient asks you if she can use aspirin
  instead, and wants to know the differences in
  prognosis between aspirin and warfarin

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Hart RG, et al. Lessons from the stroke
prevention in atrial fibrillation trials. Ann
Intern Med 2003(May 20)138831-38.

• SPAF (Stroke Prevention in Atrial Fibrillation)
  Trials
• 6 multicenter trials sponsored by NINDS
• Largest experience
• 3950 pts, 247 subjects with stroke, 7100 pt-yrs

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SPAF Trials conclusions

• SPAF I (1987)
• Ischemic stroke rate was significantly less with
  warfarin or ASA (2-3/yr) vs. placebo (6/yr)
• SPAF II (1989)
• Warfarin or ASA beneficial in elderly ( 75 yo)
• SPAF III (1990s)
• Low-dose warfarin (INR 1.2-1.5) ASA not
  effective
• Followed patients in different risk categories
• Higher risk pts benefited the most from warfarin

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SPAF III Risk Categories

• High risk pts (also valvular/rheumatic)
• Old stroke/TIA
• SBP 160
• CHF (clinical or ECHO)
• F 75 yo
• Moderate risk
• HTN
• Low risk
• none of above RFs

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SPAF data
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Perspective

• Pooled analyses (5 primary prevention trials
  SPAF, ACCP, ACC/AHA/ESC Guidelines)
• A Fib increases stroke risk 5x (4-12/yr)
• In unselected pts, warfarin ASA
• Warfarin (INR 2-3) 65 stroke reduction
  (rate close to population without A Fib)
• ASA 20 stroke reduction (mainly
  non-cardio-emb.)
• Risk stratification
• High risk pts - warfarin ASA
• Low risk pts - ASA warfarin (less benefit,
  bleeding)

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Pooled Data Concensus

• High risk factors -- use warfarin
• Valvular heart disease (esp. rheumatic/MS)
• Hx stroke/TIA
• Elderly ( 65 or 75 yo), esp. women
• CHF or LV dysfxn on ECHO
• HTN
• TEE LA thrombus, risk of LAT (Spontaneous Echo
  Contrast, decr LAA peak outflow velocity),
  complex aortic plaque
• (DM, CAD)?
• Low risk -- use aspirin ( 1/3 of all pts with A
  Fib)
• Equivalent risks in chronic vs. paroxysmal

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Stratify warfarin dosing?

• Higher stroke risk -- INR 2.5-3.5
• Prosthetic heart valve
• RHD
• Prior event
• Higher risk for bleeding -- INR 2.0-2.5
• Elderly (75 yo)

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Bottom Line

• Warfarin reduces stroke ASA in unselected
  patients
• Stratify patients into risk groups
• Identifiable risk factors use warfarin
• No risk factors use ASA instead
• Paroxysmal equivalent to chronic A. Fib

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Case

• 78 yo healthy F with A. Fib
• Elderly F high risk category
• Explain to pt that warfarin will work much better
  than ASA for her
• warfarin will decrease risk of stroke from
  8/year to 2-3, while ASA will reduce rate to
  6
• If shes still concerned, consider lowering goal
  INR to 2.0-2.5 (lower end of normal)