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Presented by Mark Pletcher, MD, MPH, at UCSF's symposium "The Role of Risk Stratification and Biomarkers in Prevention of Cardiovascular Disease" in Jan 2012.
Citation preview
The role of risk stratification and biomarkers in prevention of CVD
CVD Risk Biomarker SymposiumMark J. Pletcher, MD, MPH
1/30/2012
Objective
• Objective: – Complete translation of biomarkers into
clinical practice when beneficial
Objective
• Objective: – Complete translation of biomarkers into
clinical practice when beneficial
• Gaps: – Need evidence that will convince guideline
committees and clinicians to recommend and use the biomarker in clinical practice
– Need tools to encourage implementation and a good dissemination strategy
Outline
• Framework– Phases of evaluation of a biomarkers– Measuring health impact– RCTs and decision analysis modeling
Framework
• Objective: – Complete translation of biomarkers into clinical
practice when beneficial
• Gaps: – Need evidence that will convince guideline
committees and clinicians to recommend and use the biomarker in clinical practice
– Need tools and strategy to implement and disseminate
What KIND of evidence?
Framework
Circulation 2009;119: 2408-16.
Framework
Circulation 2009;119: 2408-16.
Association
(Discrimination)
Framework
Circulation 2009;119: 2408-16.
Reclassification
Framework
Circulation 2009;119: 2408-16.
Impact
Framework
• My thesis:
– Credible evidence of positive net health impact is and should be absolutely required
Circulation 2011;123:1116-1124
Framework
• My thesis:
– Credible evidence of positive net health impact is and should be absolutely required
• Association, discrimination, reclassification measures are not enough
• Decision analysis modeling and/or studies directly measuring health impact outcomes are required
Circulation 2011;123:1116-1124
Framework
• My thesis:
– Credible evidence of positive net health impact is and should be absolutely required
• Association, discrimination, reclassification measures are not enough
• Decision analysis modeling and/or studies directly measuring health impact outcomes are required
– Magnitude of impact and cost (i.e., cost-effectiveness) should also be considered
Circulation 2011;123:1116-1124
Framework
• 2 high profile examples
Example 1: Multimarker panel
• 10 biomarkers– CRP, BNP, homocysteine, Ualb/cr ratio, etc
• “Evaluate incremental usefulness”
NEJM 2006;355:2631-9
Example 1: Multimarker panel
• Association
NEJM 2006;355:2631-9
Example 1: Multimarker panel
• Association
NEJM 2006;355:2631-9
Example 1: Multimarker panel
• Discrimination
NEJM 2006;355:2631-9
C-statistic:
0.80 0.82
Example 1: Multimarker panel
• Conclusion
– “Adds only moderately to standard risk factors”
• Should we adopt? Abandon hope for CVD biomarkers?
NEJM 2006;355:2631-9
Example 2: CRP
• C-reactive protein
• “Compare prediction models”
Annals 2006;145:21-29
Example 2: CRP
• Association– RR-adj for ln(hsCRP) = 1.22, highly significant
Annals 2006;145:21-29
Example 2: CRP
• Association– RR-adj for ln(hsCRP) = 1.22, highly significant
• Model “fits better” with CRP– BIC improves (6969.60 6960.25)– Calibration poor without (p=.039), good with
(p=.23)
Annals 2006;145:21-29
Example 2: CRP
• Association– RR-adj for ln(hsCRP) = 1.22, highly significant
• Model “fits better” with CRP– BIC improves (6969.60 6960.25)– Calibration poor without (p=.039), good with
(p=.23)
• Discrimination improves a tiny bit– C-index 0.813 0.815– More improvement with CRP than with LDL
Annals 2006;145:21-29
Example 2: CRP
• Reclassification
Annals 2006;145:21-29
Intermediate risk ppts reclassified:
20%
(And reclassified persons’ expected risk closer to what was observed)
Example 2: CRP
• Reclassification– Might make a different treatment decision for
those 20% reclassified
Annals 2006;145:21-29
Example 2: CRP
• Conclusion
– CRP “improves cardiovascular risk classification”
• Should we adopt? Abandon hope for CRP?
Annals 2006;145:21-29
The Common Flaw
• All presented measures:– Ignore the clinical decisions they influence– Do not reflect the health consequences of
making a good vs. bad decision– Do not account for the downsides of
measuring the biomarker itself• Harm, also cost
Circulation 2011;123:1116-1124
The Common Flaw
• All presented measures:– Ignore the clinical decisions they influence– Do not reflect the health consequences of
making a good vs. bad decision– Do not account for the downsides of
measuring the biomarker itself• Harm, also cost
• Cannot estimate net health impact!
Circulation 2011;123:1116-1124
The Answer
• Measure health impact
Circulation 2011;123:1116-1124
The Answer
• Measure health impact
• Instead of:– RR, C-statistic, Hosmer-Lemeshow, IDI, NRI
• Measure:– Death, MI, fractures, disability scale, quality of
life, life-years, QALY’s
Circulation 2011;123:1116-1124
Measuring Health Impact
• It’s hard to measure health impact– Events you care about are rare– How to balance the harms against benefits?– Biomarker impact depends on specifics of the
interventions, and on the algorithm for using the biomarker
Circulation 2011;123:1116-1124
Measuring Health Impact
• It’s hard to measure health impact– Events you care about are rare– How to balance the harms against benefits?– Biomarker impact depends on specifics of the
interventions, and on the algorithm for using the biomarker
• RCTs vs. Decision/cost-effectiveness modeling (vs. both)
Circulation 2011;123:1116-1124
Measuring Health Impact
• RCTs and DCEA models– Overview– Strengths and weaknesses
Circulation 2011;123:1116-1124
Measuring Health Impact
• Randomized controlled trials (RCTs)
Study sample Randomize
Do not measure biomarker
Intervention tailored to biomarker level
Standard intervention
Measure health outcomes
Measure health outcomes
Measure biomarker
Circulation 2011;123:1116-1124
Measuring Health Impact
• Randomized controlled trials (RCTs)– Strengths: A “real-world”(?) unbiased estimate
of effectiveness• Imperfect test performance• Imperfect adherence to algorithm• Estimate portability of the intervention and
effectiveness in a specific population• Can measure utilization, unexpected downsides
Circulation 2011;123:1116-1124
Measuring Health Impact
• Randomized controlled trials (RCTs)– Weakness #1: $$$$$
• Big sample size, long follow-up– Uncommon events like MI are the most interesting...– “The Unreclassified Fraction”– Power for both upwards and downwards reclassification
• You get 1 shot at this! Choose the RIGHT algorithm– Choose the best biomarker, and best measurement method– Choose the right intervention and treatment threshold (new
drug, $generic, new evidence, new guidelines)– Strict vs. loose enforcement of the algorithm?
Circulation 2011;123:1116-1124
Measuring Health Impact
• Randomized controlled trials (RCTs)– Weakness #2: Hard to blind
• Clinicians need to know biomarker results to change treatment
• Co-interventions, biased outcome ascertainment
– Weakness #3: Long-term rare events missed• e.g., Radiation-induced cancer
Circulation 2011;123:1116-1124
Measuring Health Impact
• Decision analysis
Measuring Health Impact
• Decision analysis– Compare strategies
• Effectiveness (QALY’s, etc)• Cost ($)• Incremental cost-effectiveness ratios (ICER,
$/QALY)
Circulation 2011;123:1116-1124
Measuring Health Impact
• Decision analysis– Strengths: Relatively cheap!
• Can run lots of scenarios– Different biomarkers, different interventions, different
algorithms– Systematic approach to identifying the optimal strategy
• Sensitivity analysis for “what if…” and to identify key parameters
Circulation 2011;123:1116-1124
Measuring Health Impact
• Decision analysis– Weakness #1: “All models are wrong…”
• Imperfect evidence and estimates• Unknown/unanticipated effects • Can’t run all possible sensitivity analyses• Fundamental structure flaws
Circulation 2011;123:1116-1124
Measuring Health Impact
• Decision analysis– Weakness #2: Common metric assumptions
• Utilitarian perspective– Is it better to save the life of a young person than an old
person?
• Weighing apples vs. oranges– Quality of life/utility estimates differ, pt preferences
• Ideal strategy depends on– Willingness to pay threshold: ICER<$50,000/QALY?– Total available resources
Circulation 2011;123:1116-1124
Measuring Health Impact
• Which to use?
Measuring Health Impact
• Which to use?
• ANSWER: USE BOTH
RCT
DCEA Model
Measuring Health Impact
• ANSWER: USE BOTH– RCT
• Proof of concept• Identify unanticipated effects• Test real world implementation
– DCEA model• Systematic evaluation of strategies• Identification of key uncertainties• Synthesize evidence including long-term effects• Include cost and cost-effectiveness
Measuring Health Impact
• Comparative effectiveness iterations– 1: RCT shows treatment X is effective– 2: Cohort shows biomarker Y predicts risk– 3: Model shows test-and-treat strategy might be cost-
effective, identifies key parameters/uncertainty– 4: Observational study nails down key parameters– 5: Redo model to identify an “ideal” strategy– 6: RCT to test the “ideal” strategy shows benefit but
identifies unanticipated harm and implementation barriers
– 7: Redo model again including long-term harms and imperfect implementation: still cost-effective?…
For the rest of the day…
• Focus on:– Cardiovascular disease interventions– Biomarkers of CVD risk– Coronary calcium
• Present both RCT and DCEA plans
• Present DCEA preliminary results
• Get your feedback on theory and how to optimize
Thank you to our sponsors!
• UCSF Clinical and Translational Science Institute (CTSI)– Provided food and administrative
support
• NHLBI– Grant support!