Surrogate outcomes in liver diseases: Does making a test better make a patient better

1
Surrogate outcomes in liver diseases Does
making a test better make a patient better?

• Ronald L. Koretz, M.D.
• Emeritus Professor of Clinical Medicine
• David Geffen-UCLA School of Medicine

2
Outcomes of trials

• Effect on mortality1
• Effect on morbidity1
• Estimate of resource utilization needed2
• Effect on tests3
• 1 Primary concern of patient
• 2 Primary concern of payer
• 3 Only concern of patient/payer if it reflects
  other outcomes

3
Proving mortality effect in liver disease

• When is death an issue in liver disease?
• Fulminant hepatitis
• Decompensated cirrhosis
• Time periods
• Fulminant hepatitis days/weeks
• Decompensated cirrhosis months/years after
  cirrhosis develops
• Progression to cirrhosis - decades

4
Proving morbidity effect in liver disease

• Time course parallels mortality considerations

5
Summary of CHBG Reviews(March 2009)

• Surgical techniques1 23
• Treatment acute/acute on chronic 28
• Preventing complications cirrhosis 7
• Preventing cirrhosis 32
• Other topics2 8
• 1 Includes endoscopic/transplant issues
• 2 Immunization/biliary/screening

6
How to do a study that requires decades

• Be very patient and have understanding promotion
  committee/funding source
• Multicenter, multiple investigators
• Find outcome that requires less time

7
Outcome requiring less time

• Disease Outcome
• PBC Biochemical markers
• NASH Enzyme levels
• Hepatic fat content
• Hepatitis B/C Serologic markers
• Hemochromatosis Body iron content

8
Surrogate outcome1

• Definition Predicts a clinical outcome
• Advantages
• Occurs earlier
• Easier to measure
• Disadvantage Needs validation
• 1 Typically a test

9
Association versus causation

• I wish that they would stop turning on that
  Fasten Seat Belt sign. Every time that they
  do, the ride gets bumpy.

10
Criteria for good surrogate1

• Strong and consistent correlation between
  surrogate and clinical outcome
• Randomized trials of intervention(s) show
  consistent improvement in both surrogate and
  clinical outcomes2
• 1 Guyatt et al, Assessing a surrogate outcome
• 2 If no difference in both, cannot tell

11
Validation

• Easy to show that a surrogate factor associated
  with clinical outcome1
• Harder to show that changing the surrogate factor
  changes the clinical outcome2
• 1 Association can be demonstrated with
  observational study
• 2 Requires randomized trial with both outcomes
  measured

12
When a surrogate got it wrong

• Encainide/Flecainide/Moricizine reduced
  ventricular arrhythmias released by FDA on that
  basis
• CAST1 study RCT comparing anti-arrhythmia
  therapy to placebo after myocardial infarction
• 1 Cardiac Arrhythmia Suppression Trial

13
CAST outcomes

• Parameter Anti-arrhythmic Placebo
• Number pts 1380 1371
• 1-year mortality 10 5
• Arrest/arrhythmic 7 4
• death
• p 0.0006
• p 0.003

14
Another surrogate that wasnt

• Parenteral/enteral nutrition to treat or prevent
  morbidity associated with malnutrition

15
Studley, 1936

• Patients with gt20 body weight loss had poorer
  postoperative survival1
• 1 Association subsequently demonstrated many
  times in surgical and non-surgical disorders

16
AssumptionMalnutrition causes problems

• Consequent assumption
• Improving nutritional status will improve
  outcome
• Consequent action
• Focus on nutrition markers

17
Necessary condition for accepting a surrogate
end-point as a substitute for a clinical one

• Clinical and surrogate end-points must be
  parallel (concordant)

18
Concordance vs Discordance

• Clin EP
• Rx gt Cont Rx Cont Rx lt Cont
• Rx gt Cont C PD CD
• Nutr better Nutr better
• Nutr
• Rx Cont PD C PD
• Clin better Nutr better
• EP
• Rx lt Cont CD PD C
• Clin better Clin better
• Clin Clinical Nutr Nutritional EP
  End-point
• Rx Treatment group Cont Control group
• gt Better than lt Worse than
• C Concordance PD Partial Discordance CD
  Complete discordance

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Clinical End-points

• Mortality
• Infectious complications
• Total complications (including infectious)
• Duration of hospitalization

20
Nutritional End-points

• Protein/calorie intake
• Body weight
• Nitrogen balance
• Anthropometrics (TSF, MAC, MAMC)
• Visceral proteins (albumin, prealb, transferrin)
• Skin testing
• Total lymphocyte count
• TSF Triceps skinfold thickness MAC Midarm
  circumference MAMC Midarm muscle
  circumference prealb prealbumin

21
Summary of concordance1

• Rate of concordance lt 50 in 41/48 comparisons2
• Rates of complete discordance
• gt 25 in 43/48 comparisons
• gt 50 in 13/48 comparisons
• 1 Data from 99 RCTs
• 2 Comparing particular nutritional/clinical
  outcome

22
Concordance in trials of liver disease

• Same observation discordance was rule

23
Nutritional outcome as surrogate

• Improving nutritional end-points does not
  guarantee that clinical end-points will improve

24
Do surrogates ever work?

• HIV/AIDS viral titer, CD4 count
• 5 FU therapy for colon cancer 3 year
  disease-free survival1
• Severe hypercholesterolemia serum cholesterol
  levels
• 1 Compared to 5-year total survival

25
Surrogates in liver disease

• Bilirubin in PBC
• HCV-RNA in hepatitis C

26
Surrogates in primary biliary cirrhosis

• Alkaline phosphatase (enzyme not clinical)
• Bilirubin (function test possibly clinical)

27
PBC Bilirubin vs mortality1

• Outcome Effect 95 CI
• Mortality 1.17 (RR) 0.75, 1.82
• Bilirubin -10 (WMD) -16, -5
• 1 Yan Gong, DDW, 2006 6 trials ursodeoxycholic
  acid
• 2 micromoles/l

28
SVR and Hepatitis C

• Objective of treatment Prevent
  mortality/morbidity
• SVR is surrogate outcome that does not directly
  measure mortality or morbidity

29
Natural history of hepatitis C1

• Vast majority of patients (at least 80-90) who
  are infected by hepatitis C will never develop
  end stage liver disease
• 1 From prospective cohort studies and
  epidemiologic data

30
What does 50 SVR rate imply?

• Prognostic factors for SVR1
• Little or no fibrosis on biopsy
• Female
• Normal weight
• Cannot assume 50 reduction in subsequent
  incidence of adverse events
• 1 Factors suggesting lower likelihood to progress

31
All Viral Hepatitis Patients
Treatment Responders 50
Cirrhosis 10-20
32
SVR vs Cure

• Case reports of responders who develop
  cancer/decompensation

33
Need RCT to prove efficacy

• Problem
• Take decades to see decompensation
• Need large number in trial
• Compromise study those with severe fibrosis

34
Interferon in cirrhosisHALT-C, NEJM, 2008

• IFN1 Control
• Number patients 517 533
• Death 36 (7) 26 (5)
• Decompensated 72 (14) 69 (13)
• Number HCCs 15 (3) 15 (3)
• Surrogates2 Better
• P lt 0.05
• 1 Long-term use
• 2 ALT, histologic inflammation, SVRs

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Discordance in HALT-C

• HALT-C design did not test routine use of
  antiviral therapy
• Nonetheless, see discordance between surrogate
  and clinical outcomes
• We have to consider possibility that SVR is
  inadequate measure of treatment efficacy

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In order for a difference to be a difference, it
must make a difference

• Courtesy of John Rombeau, M.D.