cardiovascular outcome trials in diabetes and diabetes prevention measuring the balance of benefit...

Cardiovascular Outcome Trials in Diabetes Cardiovascular Outcome Trials in Diabetes and Diabetes Preventionand Diabetes Prevention

Measuring the Balance of Benefit and Risk Measuring the Balance of Benefit and Risk of Unsweetening the Bloodof Unsweetening the Blood

Robert M. Califf, MDRobert M. Califf, MDVice Chancellor for Clinical Research Vice Chancellor for Clinical Research

Duke UniversityDuke University

CV Outcome Trials in DiabetesCV Outcome Trials in Diabetes

Conceptual framework Conceptual framework

Key tradeoffsKey tradeoffs

Barriers to implementationBarriers to implementation

Consequences of status quoConsequences of status quo

Therapeutic Principles for Cardiovascular TherapeuticsTherapeutic Principles for Cardiovascular Therapeutics

Treatment effects usually modestTreatment effects usually modest

Qualitative interactions are uncommonQualitative interactions are uncommon

Quantitative interactions commonQuantitative interactions common

Unintended targets commonUnintended targets common

Long-term vs. short-term effects may differLong-term vs. short-term effects may differ

Combinations are unpredictableCombinations are unpredictable

Class effect may not be validClass effect may not be valid

Most treatments produce a mixture of benefits and risksMost treatments produce a mixture of benefits and risksCaliff and DeMets Circ 2002

Therapeutic Principles for Cardiovascular TherapueticsTherapeutic Principles for Cardiovascular Therapuetics

Most beneficial therapies do not save money, but Most beneficial therapies do not save money, but create incremental benefit for incremental costcreate incremental benefit for incremental cost

Applying the results of clinical trials is beneficialApplying the results of clinical trials is beneficial

Many areas of medicine are underserved and Many areas of medicine are underserved and therefore lack evidence to guide practicetherefore lack evidence to guide practice

Our current method of doing trials is Our current method of doing trials is unnecessarily expensiveunnecessarily expensive

Participation is criticalParticipation is criticalCaliff and DeMets Circ 2002

Therapeutics—Inescapable FactsTherapeutics—Inescapable Facts

What we know:What we know:

Systemic therapies affect multiple biological systemsSystemic therapies affect multiple biological systems

On target and off target (most of which we do not On target and off target (most of which we do not understand while the drug is being developed)understand while the drug is being developed)

How we behave:How we behave:

As if we can tell that a treatment is providing a As if we can tell that a treatment is providing a benefit by looking at one or 2 parameters (BP, Hgb benefit by looking at one or 2 parameters (BP, Hgb A1C)A1C)

Unintended TargetsUnintended Targets

TorcetrapibTorcetrapib ? Aldosterone/adrenal? Aldosterone/adrenal

TZDsTZDs BonesBones

ErythropoietinErythropoietin CV eventsCV events

Drug eluting stentsDrug eluting stents Stent thrombosisStent thrombosis



Effects of most therapies on humanly meaningful Effects of most therapies on humanly meaningful outcomes are modest so that randomization is outcomes are modest so that randomization is essential with large sample sizesessential with large sample sizes


Doctors can tell whether chronic therapies are Doctors can tell whether chronic therapies are having a net beneficial effect by their memories of having a net beneficial effect by their memories of their own patients or observing individual patientstheir own patients or observing individual patients

Post randomization databases can tell us about post Post randomization databases can tell us about post marketing treatment effectsmarketing treatment effects

Aspirin: A “Wonder” Drug

PtsRandomized Chance of Comments

Deaths (Risk = 10%) Type II Error* on Sample Size

0-50 < 500 > 0.9 Utterly inadequate

50-150 1000 0.7-0.9 Probably inadequate

150-350 3000 0.3-0.7 Possibly inadequate

350-650 6000 0.1-0.3 Probably adequate

> 650 10000 < 0.1 Adequate

PtsRandomized Chance of Comments

Deaths (Risk = 10%) Type II Error* on Sample Size

0-50 < 500 > 0.9 Utterly inadequate

50-150 1000 0.7-0.9 Probably inadequate

150-350 3000 0.3-0.7 Possibly inadequate

350-650 6000 0.1-0.3 Probably adequate

> 650 10000 < 0.1 Adequate

Sample SizeSample SizeSample SizeSample Size

Yusuf Progr CV Dis 1985Yusuf Progr CV Dis 1985

*Probability of failing to achieve p < .01 if risk reduction = 25%

9503CG019503CG01


What we knowWhat we know

The effects of therapies are context dependentThe effects of therapies are context dependent

Interactions with other treatments are common and Interactions with other treatments are common and unpredictableunpredictable

Length of treatment is importantLength of treatment is important

Clinical environment mattersClinical environment matters

How we behaveHow we behave

Drugs can be “tested” for measurement of human Drugs can be “tested” for measurement of human benefit as in a laboratory over a short period of time benefit as in a laboratory over a short period of time in any part of the worldin any part of the world



Therapies cause a mixture of benefit and harm often Therapies cause a mixture of benefit and harm often involving different organs/systems over different involving different organs/systems over different periods of timeperiods of time

How we behaveHow we behave

Short term studies done preapproval can actually Short term studies done preapproval can actually provide assurance that a drug is “safe and effective”provide assurance that a drug is “safe and effective”

Good EffectsGood EffectsGood EffectsGood Effects Bad EffectsBad EffectsBad EffectsBad Effects

Adapted from FurbergAdapted from Furberg

Therapies Always Cause a Combination Therapies Always Cause a Combination of:of:

Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time—but no difference seen in first 16 months!

Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time—but no difference seen in first 16 months!

Month

0

2

4

6

8

10

12

14

16

18 Hazard Ratio, 0.72 (95% CI, 0.56–0.93)P = .0117

Cu

mu

lati

ve I

ncid

en

ce (

%)

0 4 8 12 16 20 24 28 32 36

No. at RiskZOL 5 mg 1054 1029 987 943 806 674 507 348 237 144

Placebo 1057 1028 993 945 804 681 511 364 236 149

ZOL 5 mg (n = 1065)Placebo (n = 1062)

28%

Absolute Risk Reduction, 3.7%

The Failure of Hormone Replacement Therapy: The Failure of Hormone Replacement Therapy: Worse than neutral initially!Worse than neutral initially!

1515

1010

55

00

Estrogen + ProgestinEstrogen + ProgestinPlaceboPlacebo

Inci

denc

e (%

)In

cide

nce

(%)

Follow-Up, y (No. at Risk)Follow-Up, y (No. at Risk)

Log Rank p=0.91Log Rank p=0.91

00(2763)(2763)

11(2631)(2631)

22(2506)(2506)

33(2392)(2392)

44(1435)(1435)

55(113)(113)

HERSHERSHERSHERS WHIWHIWHIWHI

AdvertisingAdvertising

““The science of arresting the human intelligence The science of arresting the human intelligence long enough to get money from it” long enough to get money from it” — — Stephen Stephen LeacockLeacock

Hippocampus—”prescription-writing center of Hippocampus—”prescription-writing center of the brain”…”processes information by the brain”…”processes information by connecting new concepts with the parts of the connecting new concepts with the parts of the brain where gut instincts are formed, areas that brain where gut instincts are formed, areas that influence emotional behavior and form influence emotional behavior and form memories”memories”

—Advertisements that go directly to the hippocampus. Lancet 1996



Our current methods of implementing clinical trials Our current methods of implementing clinical trials are harmfully and unnecessarily bureaucratic and are harmfully and unnecessarily bureaucratic and expensiveexpensive


Since we can’t change the cost of trials we have to Since we can’t change the cost of trials we have to find shortcuts even if it jeopardizes the public healthfind shortcuts even if it jeopardizes the public health


What we know: What we know:

We all have biases and conflicts of interest that prevent We all have biases and conflicts of interest that prevent one sure answer to most clinical trial questionsone sure answer to most clinical trial questions


Companies can conduct their own trials, “hiring” Companies can conduct their own trials, “hiring” investigators without independent study investigators without independent study management and analysis of the results and management and analysis of the results and produce unbiased results or …produce unbiased results or …

If its NIH there is no biasIf its NIH there is no bias

Relation Between Statistical Significance Relation Between Statistical Significance and Publication Status in 285 Studiesand Publication Status in 285 Studies

Easterbrook, Lancet, 1991Easterbrook, Lancet, 1991

Reasons for Not Publishing 78 of 285 Reasons for Not Publishing 78 of 285 StudiesStudies Easterbrook, Lancet, 1991Easterbrook, Lancet, 1991

Copyright restrictions may apply.

Ridker, P. M et al. JAMA 2006;295:2270-2274.

Proportion of Trials Significantly Favoring Newer Treatments Over Standard of Care

Turmoil in Clinical Research:Turmoil in Clinical Research:Research Agreements between AMCs and Research Agreements between AMCs and IndustryIndustry

Do research agreements between medical Do research agreements between medical schools and industry sponsors adhere to the schools and industry sponsors adhere to the

standards embodied in the new ICMJE standards embodied in the new ICMJE guidelines?guidelines?

““We encourage investigators to use theWe encourage investigators to use therevised ICMJE requirements…to guide therevised ICMJE requirements…to guide the

negotiation of research contracts.”negotiation of research contracts.”

JAMA. 2001;286:1232-1234.JAMA. 2001;286:1232-1234.——Schulman KA, et al. NEJM 2002;347:1335Schulman KA, et al. NEJM 2002;347:1335

Conflict of Interest in Clinical Research:Conflict of Interest in Clinical Research:Research Agreements between AMCs and Research Agreements between AMCs and IndustryIndustry

Conflict of Interest in Clinical Research:Conflict of Interest in Clinical Research:Research Agreements between AMCs and Research Agreements between AMCs and IndustryIndustry

——Schulman KA, et al. NEJM 2002;347:1335Schulman KA, et al. NEJM 2002;347:1335

Impugning the Integrity of Medical ScienceImpugning the Integrity of Medical ScienceThe Adverse Effects of Industry InfluenceThe Adverse Effects of Industry InfluenceCatherine D. DeAngelis, MD, MPHCatherine D. DeAngelis, MD, MPHPhil B. Fontanarosa, MD, MBAPhil B. Fontanarosa, MD, MBA

JAMA, April 16, 2008—Vol 299, No. 15JAMA, April 16, 2008—Vol 299, No. 15

Consistency of Conflict of Interest Reporting

• Searched PubMed for English-language articles published in 2006 that provided evidence or guidance regarding the use of coronary artery stents

• Resulting database of 746 articles, 2985 authors, and 135 journals

• Recorded article characteristics, including information about authors’ financial disclosures

• Main outcome measures were the prevalence, nature, and consistency of financial disclosures

» Weinfurt KP; PLOS 1, May 7th, 2008

COI Disclosure in Stent TrialsWeinfurt KP; PLOS 1, May 7th, 2008

Comparisons Between Disclosures in Articles by the Same Author (N = 5573)

0

10

20

30

40

50

60

70

80

90

100

Absent-absent Present-present None declared-nonedeclared

Absent-none declared Present-absent Present-none-declared

Result of Comparison Between Articles

Per

cent

age

Agreement Disagreement

Interpretation

• In rare instances when financial interests were disclosed, they were not disclosed consistently, suggesting problems with transparency in the literature

• An inconsistent system of disclosure may be more harmful than no disclosure at all, because it creates the impression rather than the reality of transparency

• The relative contributions of journals and authors to this problem are unclear

Trial Organizational StructureTrial Organizational Structure

SponsorSponsorSponsorSponsorSteering CommitteeSteering CommitteeChairmen + NCs + RDs + Chairmen + NCs + RDs + experts in clinical studiesexperts in clinical studies

Steering CommitteeSteering CommitteeChairmen + NCs + RDs + Chairmen + NCs + RDs + experts in clinical studiesexperts in clinical studies

Executive Executive CenterCenter

Study ChairStudy Chair

Executive Executive CenterCenter

Study ChairStudy Chair

Coordinating Coordinating CenterCenter

Study Co-ChairStudy Co-Chair

Coordinating Coordinating CenterCenter

Study Co-ChairStudy Co-Chair

International International Data CentersData Centers

International Co-International Co-ChairChair

International International Data CentersData Centers

International Co-International Co-ChairChair

Events Review Events Review CommitteeCommittee

Events Review Events Review CommitteeCommittee

DSMBDSMBDSMBDSMB

Key Issues—Big Ticket ItemsKey Issues—Big Ticket Items

Tradeoff of Generalizability and ValidityTradeoff of Generalizability and Validity

Biological issuesBiological issues

Culture and practiceCulture and practice

Target vs DrugTarget vs Drug

Superiority/NoninferioritySuperiority/Noninferiority

Clinically important differencesClinically important differences

Trial conductTrial conduct

Sensible or nonsensical?Sensible or nonsensical?

Regulatory dysharmonyRegulatory dysharmony

Important DetailsImportant Details Enrollment criteriaEnrollment criteria

Concomitant therapyConcomitant therapyComparatorComparator

Other therapyOther therapy

Diabetes Diabetes

CV diseaseCV disease

““Diabetology” issuesDiabetology” issues““glycemic equipoise”glycemic equipoise”

DurabilityDurability

EndpointsEndpointsDefinitionsDefinitions

AdjudicationAdjudication

GeneralizabilitGeneralizabilityy

ValidityValidity

GoalGoal

XX

The pragmatic trial is really a way The pragmatic trial is really a way of finding the best compromise of finding the best compromise between validity and between validity and generalizabilitygeneralizability

Diabetes CV Outcome TrialsDiabetes CV Outcome Trials

Focused on Focused on GeneralizabilityGeneralizability

Broad entry criteriaBroad entry criteria

Broad allowance for Broad allowance for concomitant therapyconcomitant therapy

Embrace “standards of Embrace “standards of care” but avoid detailed care” but avoid detailed proscriptive protocolsproscriptive protocols

Focused on ValidityFocused on Validity

Specific entry criteria Specific entry criteria carefully measured well carefully measured well beyond what is done in beyond what is done in practicepractice

Additional therapies Additional therapies determined by protocoldetermined by protocol

Detailed protocol for Detailed protocol for clinical careclinical care

Common GroundCommon Ground

Proper consent and randomizationProper consent and randomization

Measurement of adherence/persistence to Measurement of adherence/persistence to randomized txrandomized tx

Measurement of endpoints in unbiased mannerMeasurement of endpoints in unbiased manner

What amazes me is how often industry SOP’s What amazes me is how often industry SOP’s and FDA inspectors fail to distinguish what is and FDA inspectors fail to distinguish what is important from what is fundamentally irrelevant important from what is fundamentally irrelevant to answering the question posed by the trial!to answering the question posed by the trial!

Target vs DrugTarget vs Drug

Assessing DrugAssessing Drug

Hold background Hold background constantconstant

Isolate on effects of Isolate on effects of drugdrug

CANNOT RELIABLY CANNOT RELIABLY USE SLOPE OF USE SLOPE OF TARGET/OUTCOME TARGET/OUTCOME TO ASSESS VALUE OF TO ASSESS VALUE OF TARGETTARGET

Assessing TargetAssessing Target

Achieving target is the Achieving target is the goal regardless of tx goal regardless of tx used to get thereused to get there

Understood that Understood that background tx will varybackground tx will vary

Cannot tease out Cannot tease out individual effects of individual effects of drugsdrugs

Inescapable FactInescapable Fact

We need both types of trials:We need both types of trials:

Drug trials to assess the specific balance of benefit Drug trials to assess the specific balance of benefit of risk of individual drugsof risk of individual drugs

Therapeutic target trials to understand whether in Therapeutic target trials to understand whether in general it is beneficial to drive a biomarker to a general it is beneficial to drive a biomarker to a targettarget

In the end we will always be left with some In the end we will always be left with some uncertainty about this mixuncertainty about this mix

Fundamental Trial Fundamental Trial Construct—Superiority/NoninferiorityConstruct—Superiority/Noninferiority

SuperioritySuperiority

Easy to understandEasy to understand

““Hard to imagine” that a Hard to imagine” that a tx that lowers sugar tx that lowers sugar shouldn’t reduce shouldn’t reduce macrovascular dzmacrovascular dz

Tough hurdle in Tough hurdle in comparative trialscomparative trials

NoninferiorityNoninferiority

No one can explain to No one can explain to practitionerspractitioners

Neutrality on Neutrality on macrovascular disease macrovascular disease should be sufficient if should be sufficient if glycemic effect is glycemic effect is known to be beneficialknown to be beneficial

Superiority/NoninferioritySuperiority/Noninferiority

Really a false argument—the real question is:Really a false argument—the real question is:

What is the estimated effect of the tx on the net What is the estimated effect of the tx on the net balance of risk and benefit?balance of risk and benefit?

A trial can test for both noninferiority and superiority A trial can test for both noninferiority and superiority without penalty if the trial is set up properlywithout penalty if the trial is set up properly

The real question is: The real question is:

What is the minimally important clinical difference What is the minimally important clinical difference that should be excluded in noninferiority trials and that should be excluded in noninferiority trials and exceeded in superiority trials? exceeded in superiority trials?

Minimally Important DifferenceMinimally Important Difference

Typically 10-15% relative difference or 1% Typically 10-15% relative difference or 1% absolute difference per year in ASCVD absolute difference per year in ASCVD outcomesoutcomes

Key factorsKey factors

Underlying risk (> absolute risk makes smaller Underlying risk (> absolute risk makes smaller relative difference worthwhile)relative difference worthwhile)

Cost and logistic feasibility of interventionCost and logistic feasibility of intervention

Size of population affectedSize of population affected

A treatment taken by 5 million people with 1% A treatment taken by 5 million people with 1% excess mortality per year would kill 50,000 people excess mortality per year would kill 50,000 people per yearper year

What is a Meaningful Difference in CV EndpointsWhat is a Meaningful Difference in CV Endpoints

““A difference to be a A difference to be a difference must make a difference must make a difference”difference”

? Gertrude Stein? Gertrude Stein

Sensible or Nonsensical Clinical TrialsSensible or Nonsensical Clinical Trials

Goals of medical intervention:Goals of medical intervention:

Live longer, feel better, avoid unpleasant events and Live longer, feel better, avoid unpleasant events and spend less moneyspend less money

Balance of risk and benefitBalance of risk and benefit

Surrogates can work for “on target” and “off target” Surrogates can work for “on target” and “off target” effects separately effects separately

Off target effects are ubiquitousOff target effects are ubiquitous

Clinical Trial Cost EstimatesClinical Trial Cost Estimates

$0

$50

$100

$150

$200

$250

$300

$350

$400

$450

T o tal

Co o rd in atin g Cen ter

S ite Paym en ts

Oth er

Full Cost Industry

Streamlined Industry

More Streamlined

$ In US 2007 Millions

Defining Quality in Clinical Trials

Janet Woodcock M.D.Deputy Commissioner/Chief

Medical Officer, FDAMay 10, 2007

Defining Quality

Contemporary definition: meets customer needs

Restatement: “Fitness for use” Use: customers rely on the data to make

decisionsFDA: Regulatory decisionsSponsors: Claims about productPhysicians and patients: treatment

choices IOM Workshop definition of data quality: data

good enough that decision would not change if completely accurate data used

Regulatory DysharmonyRegulatory Dysharmony

Which makes more sense?Which makes more sense?

Conducting a separate trial in every countryConducting a separate trial in every country

Conducting global trials Conducting global trials

How can we do what makes sense if regulatory How can we do what makes sense if regulatory requirements are different in every country?requirements are different in every country?

There is a perception that this problem has There is a perception that this problem has worsened in the past few yearsworsened in the past few years

Study Undertaken by FDA Study Undertaken by FDA statisticians to evaluate statisticians to evaluate possibility of systematic possibility of systematic

regional differencesregional differences Major cardiovascular outcome Major cardiovascular outcome

studies evaluated over the last 10 studies evaluated over the last 10 yearsyears

Overall study result statistically Overall study result statistically positive, ie. demonstrated overall positive, ie. demonstrated overall effecteffect

Region never pre-specified as a Region never pre-specified as a factor to be evaluated statisticallyfactor to be evaluated statistically

16 independent studies16 independent studies

difference of log-hazard ratios

Study % US

-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5

311

452

273

94

45

196

437

388

49

7410

7411

912

313

2914

1715

9016

Estimates and confidence intervals for difference between US and Non-US treatment effects for each

study

J. Lawrence

In 13 of 16 , US log hazard above 0

A figure

From the label

The Consequences of Regulatory DysharmonyThe Consequences of Regulatory Dysharmony

Given differences of opinions by regulators in Given differences of opinions by regulators in different countries the sponsor must either different countries the sponsor must either reduce countries or revert to the most reduce countries or revert to the most expensive common denominatorexpensive common denominator

This leads to a vicious cycleThis leads to a vicious cycle

If the trials are too expensive we can’t do them, If the trials are too expensive we can’t do them, therefore we’ll just have to accept or ignore therefore we’ll just have to accept or ignore uncertainty in order to enable development of uncertainty in order to enable development of new drugsnew drugs

We need a virtuous cycle of developing We need a virtuous cycle of developing common methods to reduce uncertaintycommon methods to reduce uncertainty

Enrollment CriteriaEnrollment Criteria

History of ASCVD present or absentHistory of ASCVD present or absent

ComorbiditiesComorbidities

Severity of diabetesSeverity of diabetes

On label/off labelOn label/off label

Enrollment CriteriaEnrollment Criteria

Early in disease phase Early in disease phase

More chance to “modify More chance to “modify disease”disease”

Low event rates in this Low event rates in this population (DREAM < population (DREAM < 1% /yr; NAVIGATOR 1% /yr; NAVIGATOR below expectations)below expectations)

Later in disease phaseLater in disease phase

Many more events Many more events allows shorter or allows shorter or smaller trialssmaller trials

Risk that “the horse is Risk that “the horse is out of the barn so there out of the barn so there will be no effect”will be no effect”

Concommitant TherapyConcommitant Therapy --Diabetes--Diabetes

Placebo or direct comparative trialsPlacebo or direct comparative trials

Currently no proven winnerCurrently no proven winner

Active add on vs placebo add on will be a Active add on vs placebo add on will be a viable approach for some time to comeviable approach for some time to come

As winners emerge, active control and As winners emerge, active control and combination trials will be necessarycombination trials will be necessary

Concomitant Therapy—CV RiskConcomitant Therapy—CV Risk

Risk factor controlRisk factor control

BP, lipids, smoking, exerciseBP, lipids, smoking, exercise

Secondary preventionSecondary prevention

Anitplatelet, antithrombotic, revascularizationAnitplatelet, antithrombotic, revascularization

OptionsOptions

Mandate—expensive Mandate—expensive

Recommend local guideline based careRecommend local guideline based care

On Label/Off label conundrumOn Label/Off label conundrum

Diabetes drugs are typically developed in Diabetes drugs are typically developed in narrow populations and then used broadlynarrow populations and then used broadly

If pragmatic outcome trials are limited to “on If pragmatic outcome trials are limited to “on label” use, they will not reflect actual use of the label” use, they will not reflect actual use of the drugdrug

Nor will they capture the nexus of most benefit and Nor will they capture the nexus of most benefit and harm in CV disease (the high risk population)harm in CV disease (the high risk population)

Key issues: renal dysfunction, multiple Key issues: renal dysfunction, multiple comorbidities, esp. in the elderlycomorbidities, esp. in the elderly

Glycemic EquipoiseGlycemic Equipoise

Adding a new therapy will create a difference in Adding a new therapy will create a difference in glycemia on Day 1 of the trialglycemia on Day 1 of the trial

If the goal is to examine the “non-glycemic” If the goal is to examine the “non-glycemic” benefit or harm of the treatment, the goal benefit or harm of the treatment, the goal should be to close this gap as quickly as should be to close this gap as quickly as possiblepossible

““Intensifying” the comparator brings into play Intensifying” the comparator brings into play the beneficial or detrimental effects of multiple the beneficial or detrimental effects of multiple drugsdrugs

DurabilityDurability

Many doctors want to know whether the Many doctors want to know whether the glycemic effect of the drug is a fundamental glycemic effect of the drug is a fundamental biological modification or just a suppression of biological modification or just a suppression of glucose that lasts while the drug is on boardglucose that lasts while the drug is on board

Evaluating this requires stopping the active Evaluating this requires stopping the active treatment and measuring glycemic statustreatment and measuring glycemic status

OutcomesOutcomes

““Hard” CV eventsHard” CV events

““Soft CV events”Soft CV events”

Adverse eventsAdverse events

Quality of lifeQuality of life

EconomicsEconomics

Hard EventsHard Events Death, myocardial infarction, strokeDeath, myocardial infarction, stroke

Discrete, measurable events with unarguable impact on Discrete, measurable events with unarguable impact on duration and quality of lifeduration and quality of life

DeathDeath

All cause vs CV All cause vs CV

Myocardial infarctionMyocardial infarction

As ability to measure improves many more MI cases As ability to measure improves many more MI cases relative to unstable anginarelative to unstable angina

Symptomatic vs silentSymptomatic vs silent

StrokeStroke

All cause vs ischemicAll cause vs ischemic

Imaging vs clinically evidentImaging vs clinically evident

““Soft Events”Soft Events” ACS without myocardial necrosis (unstable ACS without myocardial necrosis (unstable

angina)angina)

Diagnosis complex and difficult to verifyDiagnosis complex and difficult to verify

Majority of chest pain ED visits not UAPMajority of chest pain ED visits not UAP

RevascularizationRevascularization

Very dependent upon cultural context Very dependent upon cultural context

In a blinded trial, unbiasedIn a blinded trial, unbiased

Heart failure admissionHeart failure admission

Half way between hard and softHalf way between hard and soft

Adverse EventsAdverse Events Important events of interestImportant events of interest

Open ended adverse events will miss a large Open ended adverse events will miss a large proportion of eventsproportion of events

““Tickbox” clearly the way to goTickbox” clearly the way to go

SAE’sSAE’s

Must collect because of ubiquitous off target effects Must collect because of ubiquitous off target effects (fractures with TZDs)(fractures with TZDs)

Non-serious AEsNon-serious AEs

Focused collection via tickboxFocused collection via tickbox

Please forget open ended non-serious AE collection Please forget open ended non-serious AE collection at this point!!!at this point!!!

Cost Effectiveness:Cost Effectiveness:Conceptual GoalConceptual Goal

Year of LifeYear of Life $50-$50-100,000100,000

The Cycle of Quality: Generating Evidence to The Cycle of Quality: Generating Evidence to Inform PolicyInform Policy

Califf RM et al, Califf RM et al, Health Affairs, 2007Health Affairs, 2007

Measurement Measurement andand

EducationEducation

Measurement Measurement andand

EducationEducation

Early Translational

Steps

Early Translational

Steps

ClinicalTrials

ClinicalTrials

ClinicalPractice

Guidelines

ClinicalPractice

Guidelines

PerformanceMeasures

PerformanceMeasures

OutcomesOutcomes

Discovery ScienceDiscovery Science

DataDataStandardsStandards

DataDataStandardsStandards

NetworkNetworkInformationInformation

NetworkNetworkInformationInformation

EmpiricalEmpiricalEthicsEthics

EmpiricalEmpiricalEthicsEthics

PrioritiesPrioritiesand Processesand Processes

PrioritiesPrioritiesand Processesand Processes

InclusivenessInclusivenessInclusivenessInclusiveness

Use forUse forFeedbackFeedback

on Prioritieson Priorities

Use forUse forFeedbackFeedback

on Prioritieson Priorities

Conflict-of-interestConflict-of-interestManagementManagement

Conflict-of-interestConflict-of-interestManagementManagement

Evaluation of SpeedEvaluation of Speedand Fluencyand Fluency

Evaluation of SpeedEvaluation of Speedand Fluencyand Fluency

Pay forPay forPerformancePerformance

Pay forPay forPerformancePerformance

TransparencyTransparencyto Consumersto ConsumersTransparencyTransparencyto Consumersto Consumers

FDAFDACritical PathCritical Path

FDAFDACritical PathCritical Path

NIH RoadmapNIH RoadmapNIH RoadmapNIH Roadmap12 3

4

5

6

7

8

910

11

12

The Key in ACS is doing the right trialsThe Key in ACS is doing the right trials Reduction in deaths:Reduction in deaths:

TherapyTherapy # pts# pts RelativeRelative AbsoluteAbsolute C/EC/E

MI:MI: AspirinAspirin 18,77318,773 23%23% 2.4%2.4% ++++++++++

FibrinolyticsFibrinolytics 58,00058,000 18%18% 1.8%1.8% ++++++++

Beta blockerBeta blocker 28,97028,970 13%13% 1.3%1.3% ++++++++

ACE inhibitorACE inhibitor 101,000101,000 6.5%6.5% .6%.6% ++

2nd prev: Aspirin 54,360 15% 1.2% +++++

Beta blocker 20,312 21% 2.1% ++++

StatinsStatins 17,61717,617 23%23% 2.7%2.7% ++++++++

ACE inhibitor 9,297 17% 1.9% ++++

CHF: ACE inhibitor 7,105 23% 6.1% +++++

Beta blocker 12,385 26% 4% +++++

SpironolactoneSpironolactone 1,6631,663 30%30% 11%11% ++++++++++

Given the Right Trials, Adherence Matters!Given the Right Trials, Adherence Matters!Improve Adherence to ACC/AHA Guidelines for Improve Adherence to ACC/AHA Guidelines for Patients with Unstable Angina/Non-STEMIPatients with Unstable Angina/Non-STEMI

Acute TherapiesAcute Therapies

AspirinAspirin

ClopidogrelClopidogrel

Beta BlockerBeta Blocker

Heparin (UFH or LMWH)Heparin (UFH or LMWH)

Early CathEarly Cath

GP IIb-IIIa InhibitorGP IIb-IIIa Inhibitor

All receiving cath/PCIAll receiving cath/PCI

Discharge TherapiesDischarge Therapies

AspirinAspirin

ClopidogrelClopidogrel

Beta BlockerBeta Blocker

ACE Inhibitor ACE Inhibitor

Statin/Lipid LoweringStatin/Lipid Lowering

Smoking CessationSmoking Cessation

Cardiac RehabilitationCardiac Rehabilitation

Circulation, JACC 2002 — ACC/AHA Guidelines updateCirculation, JACC 2002 — ACC/AHA Guidelines update

Evaluating the Process of CareEvaluating the Process of Care

An adherence score is applied to each patient. An adherence score is applied to each patient. incorporating the components of process of care.incorporating the components of process of care.

The score from each patient then combined for all The score from each patient then combined for all patients at each hospital. patients at each hospital. Typical scores ranged from 50 to 95%.Typical scores ranged from 50 to 95%.

All 400 hospital adherence scores then ranked in All 400 hospital adherence scores then ranked in quartiles — best to worst.quartiles — best to worst.

Evaluating the Process of CareEvaluating the Process of Care

An adherence score is applied to each patient. An adherence score is applied to each patient. incorporating the components of process of care.incorporating the components of process of care.

The score from each patient then combined for all The score from each patient then combined for all patients at each hospital. patients at each hospital. Typical scores ranged from 50 to 95%.Typical scores ranged from 50 to 95%.

All 400 hospital adherence scores then ranked in All 400 hospital adherence scores then ranked in quartiles — best to worst.quartiles — best to worst.

Overall Adherence Score Trends Over TimeOverall Adherence Score Trends Over Time

68.1%69.6%

71.0%72.3%

73.0% 73.6%75.2%

77.9% 78.0%79.3%

60%

70%

80%

Q1'02

Q4'02

Q3'03

Q2'04

Peterson et al, ACC 2004Peterson et al, ACC 2004

Applying High Quality Evidence Improves Applying High Quality Evidence Improves OutcomesOutcomes

0

2

4

6

8

<=25% 25–50% 50–75% >=75%

Hospital Composite Quality Quartiles

% In

-ho

spit

al M

ort

alit

y Adjusted Unadjusted

Every 10% in guidelines adherence 11% in mortality

The Cycle of QualityThe Cycle of Quality

We should be able to do this in diabetesWe should be able to do this in diabetes

The key is high quality pragmatic trials that The key is high quality pragmatic trials that measure the balance of benefit and risk!measure the balance of benefit and risk!

Alternatives to EBMAlternatives to EBM

Eminence-based medicineEminence-based medicine

Confidence-based medicineConfidence-based medicine

Eloquence-based medicineEloquence-based medicine

Vehemence-based medicineVehemence-based medicine

Providence-based medicineProvidence-based medicine

Diffidence-based medicineDiffidence-based medicine

Nervousness-based medicineNervousness-based medicine

Isaacs D, Fitzgerald D. Br Med J 1999;319:1618.

All others must have All others must have data!data!

“and when you get “and when you get the data you find its the data you find its not as simple as what not as simple as what you believed when you believed when you had no data”you had no data”H Gerstein 2008H Gerstein 2008

cardiovascular outcome trials in diabetes and diabetes prevention measuring the balance of benefit...

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