Journal Update August 2004

1
Journal UpdateAugust 2004

• Soma Wali, MD
• Michael Rotblatt, MD
• Olive View-UCLA Medical Center

2
Journal Update

• Update housestaff and faculty on recent
  literature
• Review last 1-2 months of
• NEJM, Ann Intern Med, JAMA, Lancet, etc.
• Select 2 articles/month
• Prospective DBRCTs or other important articles
• Different than Journal Club (in addition to)

3
Todays topics...

• Prostate cancer and normal PSA
• New guidelines for tx of hyperlipidemia
• Pharmaceutical Update

4
Case 1

• 58 year old M with h/o HTN presents for routine
  follow up
• Lab results from a previous visit shows a normal
  lipid panel and a PSA3.8
• You share the results with the pt and he asks
• Does this mean that I dont have prostate
  cancer?
• With what assurance can you tell the patient that
  this test means he doesnt have prostate cancer?

5
Background

• Prostate Ca is the second leading cause of cancer
  death among men
• For an American male, the lifetime risk of
  developing prostate Ca is 16
• The risk of dying of prostate Ca is only 3
• Prostate Ca is easily detectable, often grows
  very slowly
• Most men die of other causes before prostate Ca
  becomes clinically advanced

6
Background

• Screening Tests
• First Line
• Digital Rectal Examination (DRE)
• Serum PSA
• Diagnostic Tests
• Transrectal Ultrasound (TRUS)
• Biopsy

7
Digital Rectal Exam (DRE)

• Can detect tumors in the posterior and lateral
  aspects of the prostate gland
• Cannot detect Stage T1 CA that is non-palpable
• The PPV varies from 5 to 30 without a PSA, but
  increases when combined with a PSA
• The NPV is lower due to examiner experience
• No controlled studies have shown a reduction in
  the MM of prostate Ca when detected by DRE at
  any age
• The greatest value of DRE may be its use in
  combination with PSA testing

8
Prostate Specific Antigen (PSA)

• A glycoprotein expressed by epithelial cells
• Prostate Ca expresses more PSA per gram than
  normal or hyperplastic prostate tissue
• In addition, cancerous tissue may disrupt the
  prostate blood barrier, further increasing serum
  PSA
• PSA is the most sensitive noninvasive test
  available for early detection of prostate Ca
• Levels gt 4.0 ng/mL abnormal (and lt 4.0 nl)
• However, elevations are neither specific nor
  sensitive for prostate Ca
• PSA is elevated in BPH, prostatitis and advanced
  age

9
Thompson et al. Prevalence of prostate Ca among
men with a PSA level lt 4 ng/mL.NEJM. May 27,
20043502239

• Purpose To determine the predictive value of PSA
  in the (normal) range of 0.0 - 4.0 ng/mL
• Investigated the prevalence of prostate Ca among
  men in the Prostate Cancer Prevention Trial
  (PCPT) who had a PSA level of lt 4 ng/mL

10
Method

• The PCPT was a R-DB-PC study designed to
  determine whether treatment with 5mg/dy of
  finasteride could reduce the prevalence of
  prostate Ca during a 7 year period
• (Results already published last year)
• N 18,882
• Eligibility criteria
• A baseline serum PSA of lt 3 ng/mL
• A normal DRE
• Age gt 55
• No clinical sig coexisting conditions

11
Method

• At the end of the 7 year study, participants
  without a dx of Prostate Ca were scheduled for Bx
  (and a PSA)
• 9459 men were randomly assigned to the PCPT
  placebo group, which was used for this current
  study
• 6509 excluded due to PSAgt4, abnormal DRE, no
  end-of-study Bx, or death

12
Results

• 2950 men (age 62-91) with PSA lt 4 and normal DRE
  were included in the final analysis
• 449 (15.2) had prostate Ca at end-of-study Bx,
  despite PSA lt 4 ng/mL and normal DRE
• 67 high grade (Gleason score gt7) 15 of CAs

13
Results

• 449 patients (15) dxed with prostate Ca
• PSA levels Ca Prevalence High grade CA
• 0.0-0.5 ng/mL 6.6 4/32 (12.5)
• 0.6-1.0 ng/mL 10.1 8/80 (10)
• 1.1-2.0 ng/mL 17 20/170 (12)
• 2.1-3.0 ng/mL 23.9 22/115 (19)
• 3.1-4.0 ng/mL 26.9 13/52 (25)

14
Results

• FH of prostate Ca was significantly associated
  with increased risk of prostate Ca
• Age and race at Bx was not statistically sig
• Prevalence of high grade cancers increased from
  12.5 associated with a PSA level of 0.5 ng/mL to
  25 with a PSA level of 3.1- 4 ng/mL
• Age range 61-79

15
Authors Conclusions

• Biopsy-detected prostate Ca, including high grade
  cancers, is not rare among men with PSA levels lt
  4.0 ng/mL
• These were levels generally thought to be in the
  normal range
• A decision to lower the current PSA threshold for
  Bx should be considered within the broader
  context of the PSA-Screening debate

16
Perspectives

• Prostate Ca that has spread to the capsule is not
  curable with radiation, hormones, or chemo
• The only way to decrease the mortality of
  prostate Ca is detecting it at an early stage
• However, prostate screening has generated
  considerable controversy, and has resulted in
  widely variable authoritative recommendations

17
Perspectives

• The Quebec Screening study randomly assigned men
  to screening or no screening (DRE and PSA) and
  compared mortality over time
• 137 deaths due to prostate Ca in 38,056
  unscreened (0.36)
• 5 deaths in 8137 screened (0.06)
• Difference 50 vs. 15 deaths per 100,000
  man-years
• Authors concluded that early dx and Tx
  dramatically decreased deaths from prostate Ca

18
Perspectives

• Arguments in favor of screening
• PSA screening detects clinically important Ca
• The discovery of elevated PSA levels advanced the
  detection of aggressive Ca by an average of 5.4
  years
• Multiple reports show a significant decrease in
  mortality from prostate Ca between 1988-1998
• In a prospective study of gt10,000, those screened
  with PSA were dxed with organ confined tumors

19
Perspectives

• Arguments against Screening
• A positive screening test may lead to large
  numbers of men having side effects from therapy
  for prostate Ca, with little or no benefit in Ca
  MM
• Rad prostatectomy adverse effects Urinary
  incontinence, impotence, perioperative deaths
  (very low)
• Tx for early stages may not have an impact on
  overall and cause specific survival especially in
  men with low grade cancers or comorbidities

20
Perspective

• Argument against screening
• White American men have a 2.1 fold greater risk
  of being dxed with prostate Ca than British
  white men
• This is due to little prostate cancer screening
  in Britain
• However, the risk of death from prostate Ca is
  nearly identical in these two populations (i.e.,
  screening makes no difference?)

21
Perspective

• Unpublished controversial data
• At the last AUA annual meeting, data presented
  that PSA levels in the last 5 years are
  correlated only with BPH, not with prostate
  cancer
• Histologic study of every untreated prostate
  removed by radical prostatectomy at Stanford
  Univ. Hospital since 1983 (n1317)
• 1983-1988 PSA highly related to histologic CA
  parameters
• 1999-2003 PSA related only to prostate size
• ????

22
Perspective

• After reviewing the literature and evidence
• Although it would be desirable to detect the
  small proportion of of high grade Ca in men with
  low PSA levels, lowering the PSA normal range
  will not be helpful
• High grade Ca usually produces low PSA levels
• Prostate Ca detected at lower PSA levels are more
  likely to have a small volume and be clinically
  insignificant NEJM editorialist
• Lowering the cut-off would also vastly increase
  the number of screeing BXs needed

23
Screening Guidelines, examples

• American Cancer Society
• PSA and DRE offered annually to men gt 50 y.o. who
  have a life expectancy of 10 years, at age 45 in
  pts with risk factors, and in pts who ask
  physicians to make the decision for them
• U.S Preventive Task Force and many European
  Cancer Societies
• Have not endorsed routine PSA screening
• American College of Physicians
• Describe the potential benefits harms of
  screening, dx and treatment, listen to the pts
  concerns, and individualize the decision to screen

24
Our Bottom Line

• Screening for prostate Ca using PSA is still very
  controversial
• PSA is not a reliable test due to high false
  positive and false negative results
• This study provides more evidence that PSA is far
  from an ideal tool
• Not just because of false
• Also clinically significant false negative results

25
Case 1

• 58 year old male presents with PSA 3.8
• The patient asks if this means that he doesnt
  have prostate Ca
• What do you tell the patient?
• Prostate Ca is very unlikely, but a normal PSA
  can not rule out prostate Ca
• There is no absolute cut off point
• Other things to do if patient is worried (FH,
  other Ca?)
• DRE if positive consider Bx
• Follow rate of PSA rise over time
• In the future, discuss the risks and benefits of
  PSA with the pt before ordering the test

26
Case 2

• LF, a 67 yo WM with CAD and DM is seen in clinic
• Among other meds, he takes simvastatin 40 mg
  daily
• Total Chol 190 - HgA1c 9.8
• LDL 92
• HDL 48
• TG 195
• Lipid panel appears acceptable, but your
  attending says there are new official lipid
  guidelines
• What are the new guidelines?

27
Background

• NCEP Expert Panel on Detection, Evaluation and Tx
  of High Blood Cholesterol in Adults
• Adult Treatment Panel (ATP) q 5 yrs
• ATPIII - exec summary 5/01, full report 12/02
• Data from 5 large RCTs with statins
• Statins only class to decrease total mortality
  in primary and secondary prevention studies

28
ATPIII Risk Assessment

• Fasting lipid panel
• Identify CHD
• Or CHD equivalents (non-coronary atherosclerotic
  dis, DM)
• Determine Framingham CRFs score
• Age (M gt 45, F gt 55)
• FH of premature CHD (M 1st deg rel. lt 55, F lt 65)
• Cigs
• HTN (gt 140/90, or on meds)
• HDL lt 40 for HDL gt 60, subtract one CRF
• For gt 2 CRFs w/o CHD ---gt calc. 10 yr CHD risk

29
ATPIII Risk Assessment...

• LDL Goals
• LDL lt 100 CHD/CHD equivalents gt 2
  CRFs with 10 yr CHD risk gt 20
• LDL lt 130 gt 2 CRFs (with 10 yr CHD risk lt 20)
• LDL lt 160 0-1 CRFs (10 yr CHD risk lt 10)
• --------------------------------------------------
  ----------------------
• Secondary goal if TG gt 200
• Non-HDL-C (TC - HDL) goal 30 gt LDL goal

30
Grundy et al. Implications of recent clinical
trials for the National Cholesterol Education
Program ATPIII GuidelinesCirculation. July 13,
2004110227-239

• Reviewed 5 major RCTs published since ATPIII
• Addressed issues not adequately assessed in
  previous RCTs
• Changed recommendations for certain categories of
  patients

31
5 newer RCTs

• HPS (Lancet 2002)
• 20,536 adults w/CHD or equiv. calc LDL 150
• Simvastatin 40 mg --gt decr total
  mortality/sub-categ
• RRR in all categories of patients
• DM w/o CHD, direct LDL gt135, lt 116, lt100
• PROSPER (Lancet 2002)
• 5804 elderly (70-82 yo) vasc dis or CRFs
• Pravastatin 40 mg --gt decr most mort/morb
  categories, except stroke risk

32
5 newer RCTs...

• ALLHAT-LLA (JAMA 2002)
• 10,355 adults 1/2 DM/CHD HTN gt 1 CRF
• LDL 100-130 gt120
• Mortality Pravastatin usual care
• Unblinded, no placebo control
• ASCOT-LLA (Lancet 2003)
• 19,342 adults HTN gt 3 other CRFs LDL 132
• Atorvastatin 10 mg
• Halted early decr mortal subcateg/trend total
  mortal

33
5 newer RCTs...

• PROVE IT (NEJM 2004)
• 4,162 adults hospitalized for ACS w/in past 10
  dys
• Atorvastatin 80mg vs. pravastatin 40mg x 2 yrs
• Decr composite end-point (death/MI/UA/CVA) with
  atorvastatin by 16 (Plt0.005) --gt 4 ARR
• Trend for total mortality
• Pravastatin --gt LDL 95
• Atorvastatin --gt LDL 62

34
Unpublished study results...

• Collaborative Atorvastatin DM Study (CARDS)
• 5 yr study evaluating Atorvastatin 10 mg vs.
  placebo for primary prevent. of CV events in DM2
  ( gt1 CRF)
• Halted one year early due to superiority of
  atorvastatin
• 37 RRR in major CV events
• NNT 27 over 4 years
• Same RRR regardless of baseline lipids (same for
  high and low LDL values), although LDLlt100 were
  not examined
• Consistent with new ACP guidelines to use
  statins, regardless of LDL value, in DM2 ( 1
  other CRF)

35
Perspective

• Epidemiologic log linear relationship
• Statins 11 --gt decr LDL 30-40 --gt 30-40
  decr in CHD risk over 5 yrs
• HPS confirms this relationship clinically at low
  LDL levels
• ATPIII based LDL goal lt 100 on
• RCTs that achieving LDL lt 100
• Practical reduction with usual statin doses

36
Authors Recommendations (Official NCEP/ATPIII
addendum)

• Use a dose to achieve LDL decr gt 30-40
• Wasteful to use minimal dose to produce small RRR
• For high risk pts
• Recommended goal still lt 100
• Goal of lt 70 is an option in very high risk pts
  (clinical judgment to weigh benefits, safety,
  cost)
• CVD multiple CRFs (esp DM), severe/poorly
  controlled CRFs, Metabolic Syndrome, ACS
• Limitations baseline LDL gt 150-160 (may need gt
  1 drug)
• High TG/low HDL, consider adding fibrate or niacin

37
Our Bottom Line

• In very high risk patients, goal lt 70-80 is
  reasonable, using statins
• Atorvast, rosuvast gt simvast gt lovast, pravast,
  fluvast
• No studies have documented that statins other
  drugs affect mortality in this same log linear
  fashion
• Statin MOA decr lipids vs. other?
• Other MOAs plaque stabilization, reversal of
  endothelial dysfxn, decr thrombogenicity, decr
  inflammation
• If cant reach LDL lt 70-80 with statins alone,
  recommendation to use multiple drugs currently is
  not directly supported by controlled trials

38
Current Pending Studies

• Large study populations (n10,000) with gt 5 year
  f/u
• TNT (CHD pts)
• Atorvastatin 10 mg vs. 80 mg (LDL 100 --gt 75)
• IDEAL (CHD pts)
• Simvastatin 20-40 mg vs. Atorvastatin 80 mg
• SEARCH (CHD pts)
• Simvastatin 20 vs. 80 mg
• ACCORD (DM)
• Simvastatin 20 mg vs. Simvastatin/fenofibrate

39
Case 2

• LF, a 67 yo WM with CAD, poorly controlled DM, on
  simvastatin 40mg
• Total Chol 190 - HDL 48
• LDL 92 - TG 195
• New NCEP/ATPIII guidelines?
• Very high risk pt, thus intensive therapy is a
  reasonable option to reach goal LDL lt 70-80
• Increase simvastatin to 80 mg
• Switch to atorvastatin 80 mg
• Switch to rosuvastatin 40 mg (non-formulary)
• ?? Addition of ezitimibe, niacin, fibrate an
  option

40
Pharmaceutical Update
41
New Drugs

• Trospium Chloride (Sanctura(R))
• Antispasmodic, antimuscarinic agent
• For tx of overactive bladder (sxs incontinence,
  urgency, urinary frequency)
• Dose 20mg BID, on an empty stomach
• 10 absorbed, decreased 75 with food t1/2 18
  hours renally excretion
• SEs dry mouth, (constipation) dose limiting
  effect
• Similar to oxybutinin (Ditropan), tolterodine
  (Detrol)
• Lansoprazole (Prevacid(R)) IV formulation
• Erosive esophagitis in pts who are NPO

42
Glitazones for psoriasis?

• Anecdotal cases of psoriasis improving when
  diabetics started a glitazone (rosiglitazone or
  pioglitazone)
• Preliminary studies appear to show benefits
• Glitazones activate Peroxisome Proliferator-Activa
  ted Receptors (PPARs)
• anti-inflammatory, immune-modulatory,
  anti-obesity, anti-lipid effects

43
Medical Letter Aug 2, 2004

• Ibuprofen may interfere with the
  cardio-protective effects of ASA
• When ibuprofen is given ATC or with low dose ASA,
  various studies demonstrate decreased ASA
  benefits
• Inhibits antiplatelet effects in healthy subjects
• More CV disease in some epidemiologic studies
• ASA effects not affected
• by COX-II inhibitors, tylenol, diclofenac
• if ibuprofen ingested gt 2 hrs after ASA

44
Match the animal with the medical use...

• Leeches
• Pork whipworm
• Puffer fish

• Investigational analgesic
• Beneficial for IBD?
• FDA approved for healing skin grafts

45
Leeches

• Used in blood-letting for 1000s of years
  height of medicinal use in mid-1800s
• Now FDA approved as a tool for healing skin
  grafts or restoring circulation
• approved as a medical device
• Particularly useful in surgeries to reattach body
  parts such as fingers or ears - leeches can help
  restore blood flow to reconnected veins
• French Firm, Ricarimpex SAS
• Company has been breeding leeches for 150 yrs

46
Puffer fish

• Tetrodotoxin poison from the puffer fish is an
  effective analgesic via IM injection in a small
  22 pt trial
• Highest dose used 20 mcg TID
• Tested in refractory cancer pain
• All types of pain appeared to respond -
  neuropathic, somatic, visceral
• SEs tingling/numbness, nausea, ataxia
• Canadian company begun full-scale clinical trial

47
Pork whipworm

• Worms for IBD?
• Hypothesis helminths have beneficial immune
  modulating properties U. Iowa GI division
• 2,500 Trichuris suis (porcine whipworm) eggs
  ingested by Crohns or UC patients every 2-3
  weeks for 24 weeks
• Disease Activity Score
• 48 response rate - helminths
• 15 response rate - placebo