Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs

Issues with Issues with the statistical analyses in the the statistical analyses in the citizen’s petition for aspirin on citizen’s petition for aspirin on reduction of the risk of 1reduction of the risk of 1stst MI MI

Chenxiong (Charles) Le, Ph.D.Chenxiong (Charles) Le, Ph.D.

OBI/OB/OPaSS/CDER, FDAOBI/OB/OPaSS/CDER, FDA

Cardiovascular and Renal Drugs Cardiovascular and Renal Drugs

Advisory Committee Meeting Advisory Committee Meeting

December 8, 2003December 8, 2003

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OutlineOutline

BackgroundBackground

Sponsor’s ‘meta-analysis’Sponsor’s ‘meta-analysis’

HOT study issuesHOT study issues

Pooled analysis issuesPooled analysis issues

Exploratory benefit-risk analysisExploratory benefit-risk analysis

SummarySummary

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The Sponsor requested amendment to the The Sponsor requested amendment to the Professional Labeling for aspirin Professional Labeling for aspirin Indication: Low dose aspirin (75 mg – 325 Indication: Low dose aspirin (75 mg – 325 mg) reduces the risk of a 1mg) reduces the risk of a 1stst myocardial myocardial infarction (MI) in patients with a CHD risk infarction (MI) in patients with a CHD risk of 10% or greater over 10 years, or there of 10% or greater over 10 years, or there is a positive benefit-risk as assessed by is a positive benefit-risk as assessed by their health care providertheir health care providerFive studies were selected to support this Five studies were selected to support this citizen’s petitioncitizen’s petition

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Five studiesFive studies– (BDT) British Doctor’s Trial (N=5139)(BDT) British Doctor’s Trial (N=5139)– (PHS) Physician’s Health Study (N=22071)(PHS) Physician’s Health Study (N=22071)

– (TPT) Thrombosis Prevention Trial (N=5085)(TPT) Thrombosis Prevention Trial (N=5085)– (HOT) Hypertension Optimal Treatment Study (HOT) Hypertension Optimal Treatment Study

(N=18790)(N=18790)– (PPP) Primary Prevention Project (N=4495)(PPP) Primary Prevention Project (N=4495)

Total # of subjects = 55580Total # of subjects = 55580

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BackgroundBackground The agency considered aspirin (BDT and The agency considered aspirin (BDT and PHS) for this indication before and did not PHS) for this indication before and did not approve itapprove it– PHS showed that some patients had a prior MI PHS showed that some patients had a prior MI

and aspirin is already known to reduce the risk and aspirin is already known to reduce the risk of recurrent MIof recurrent MI

– PHS did not achieve statistical significance PHS did not achieve statistical significance when all deaths as well as nonfatal MI and when all deaths as well as nonfatal MI and stroke were combinedstroke were combined

– BDT, despite its similarity to PHS, was neutral BDT, despite its similarity to PHS, was neutral on the effect of aspirin on MIon the effect of aspirin on MI

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What is new in this petition?What is new in this petition?– Three new studies (TPT, HOT, PPP) were Three new studies (TPT, HOT, PPP) were

includedincluded– HOT (N = 18790) is the largest among the HOT (N = 18790) is the largest among the

three studies (TPT, N = 5085, PPP, N = 4495)three studies (TPT, N = 5085, PPP, N = 4495)– Sponsor’s ‘Meta-analysis’ of the five studies Sponsor’s ‘Meta-analysis’ of the five studies

was submitted to support the petitionwas submitted to support the petition

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Sponsor’s ‘meta-analysis’Sponsor’s ‘meta-analysis’Nonfatal MI Nonfatal MI

AspirinAspirin ControlControlnn NN nn NN

PHSPHS 129129 1103711037 213213 1103411034

BDTBDT 8080 34293429 4141 17101710

TPTTPT 9494 25452545 137137 25402540

HOTHOT …… …… …… ……

PPPPPP 1515 22262226 2222 22692269

TotalTotal 318318 1923719237 413413 1755317553

RR RR

(95%CI)(95%CI)

0.680.68

(0.59-0.79)(0.59-0.79)

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Sponsor’s ‘meta-analysis’Sponsor’s ‘meta-analysis’Composite of MI, stroke and CV deathComposite of MI, stroke and CV death


PHSPHS 307307 1103711037 370370 1103411034

BDTBDT 289289 34293429 147147 17101710

TPTTPT 228228 25452545 260260 25402540

HOTHOT 315315 93999399 368368 93919391

PPPPPP 4747 22262226 7171 22692269

TotalTotal 11861186 2863628636 12161216 2694426944

RR RR (95%CI)(95%CI)

0.850.85

(0.79-0.93)(0.79-0.93)

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Sponsor’s ‘meta-analysis’Sponsor’s ‘meta-analysis’Cardiovascular deathCardiovascular death


PHSPHS 8181 1103711037 8383 1103411034

BDTBDT 148148 34293429 7979 17101710

TPTTPT 101101 25452545 8181 25402540

HOTHOT 133133 93999399 140140 93919391

PPPPPP 1717 22262226 3131 22692269

TotalTotal 480480 2863628636 414414 2694426944

RR RR (95%CI)(95%CI)

0.980.98

(0.85-1.12)(0.85-1.12)

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The HOT study The HOT study Silent MI mattersSilent MI matters

Primary endpoint was major CV events Primary endpoint was major CV events (non-fatal and (non-fatal and silent MIsilent MI, non-fatal stroke, , non-fatal stroke, and cardiovascular death) and cardiovascular death)

Silent MIs were obtained by comparing the Silent MIs were obtained by comparing the ECGs at baseline and final visit ECGs at baseline and final visit

n=9399 in aspirin and n=9391 in placebon=9399 in aspirin and n=9391 in placebo

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The HOT studyThe HOT studySilent MI mattersSilent MI matters

There were 48% and 31% silent MIs in the There were 48% and 31% silent MIs in the aspirin group and placebo group, respectivelyaspirin group and placebo group, respectively

AspirinAspirinn (%)n (%)

PlaceboPlacebon (%)n (%)

Silent MISilent MI 75 (48)75 (48) 57 (31)57 (31)

Other MIOther MI 82 (52)82 (52) 127 (69)127 (69)

Total MITotal MI 157 157 184184

Note: 14% of the patients’ ECGs were not available .

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The HOT study The HOT study Silent MI mattersSilent MI matters

EndpointEndpoint

AspirinAspirinN=9399N=9399n (%)n (%)

PlaceboPlaceboN=9391N=9391n (%)n (%)

P-P-ValueValue

RRRR(95% CI)(95% CI)

Major CV events Major CV events 388 (4.1)388 (4.1) 425 (4.5)425 (4.5) 0.170.17 0.91 (0.79-1.04)0.91 (0.79-1.04)

Major CV events (- Silent MI)Major CV events (- Silent MI) 315 (3.4)315 (3.4) 368 (3.9)368 (3.9) 0.030.03 0.85 (0.73-0.99)0.85 (0.73-0.99)

All MI All MI 157 (1.7)157 (1.7) 184 (2.0)184 (2.0) 0.130.13 0.85 (0.69-1.05)0.85 (0.69-1.05)

All MI (- Silent MI )All MI (- Silent MI ) 82 (0.9)82 (0.9) 127 (1.4)127 (1.4) 0.0020.002 0.64 (0.49-0.85)0.64 (0.49-0.85)

All StrokeAll Stroke 146 (1.6)146 (1.6) 148 (1.6)148 (1.6) 0.880.88 0.98 (0.78-1.24)0.98 (0.78-1.24)

CV MortalityCV Mortality 133 (1.4)133 (1.4) 140 (1.5)140 (1.5) 0.650.65 0.95 (0.75-1.20)0.95 (0.75-1.20)

Total MortalityTotal Mortality 284 (3.0)284 (3.0) 305 (3.2)305 (3.2) 0.360.36 0.93 (0.79-1.09)0.93 (0.79-1.09)

Source: Final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998Source: Final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998

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The HOT study issuesThe HOT study issues

The published paper reported that statistical The published paper reported that statistical significance was achieved for the composite significance was achieved for the composite endpoint of non-fatal MI, non-fatal stroke, and endpoint of non-fatal MI, non-fatal stroke, and CV death, and for MI alone. This is misleadingCV death, and for MI alone. This is misleading

Silent MIs should be included in both efficacy Silent MIs should be included in both efficacy endpoints according to the study protocol endpoints according to the study protocol

When silent MIs are included, both the When silent MIs are included, both the primary endpoint (non-fatal & silent MI, non-primary endpoint (non-fatal & silent MI, non-fatal stroke, and CV death) and MI alone are fatal stroke, and CV death) and MI alone are not statistically significantnot statistically significant

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Pooled analysis Pooled analysis Studies’ summaryStudies’ summary

PHSPHS BDTBDT TPTTPT HOTHOT PPPPPP

Total NTotal N 2207122071 51395139 50855085 1879018790 44954495

Ave. FollowupAve. Followup 2.52.5 ?? ?? 3.83.8 3.63.6

Patient Patient PopulationPopulation

Healthy Healthy male male MDMD

Healthy Healthy male male MDMD

Male at Male at high risk high risk of CVDof CVD

Pts /DBP Pts /DBP from from

100-115 100-115 mmHgmmHg

Pts / one Pts / one or more or more CV risk CV risk factorfactor

Age RangeAge Range 40-8440-84 50-7850-78 45-6945-69 50-8050-80 50-80+50-80+

FemaleFemale 00 00 00 8883/47.38883/47.3 1912/42.51912/42.5

DoseDose 325 mg 325 mg QODQOD

500 mg 500 mg QDQD

75 mg 75 mg QDQD

75 mg 75 mg QDQD

100 mg 100 mg QDQD

Source: FDA’s clinical review by Dr. Juan Carlos Pelayo.

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Pooled analysisPooled analysis

The patient populations were quite The patient populations were quite different among the 5 studies (ranging different among the 5 studies (ranging from apparently healthy physicians to from apparently healthy physicians to patients at high risk of CV disease)patients at high risk of CV disease)

Aspirin doses vary from 75 mg daily to 500 Aspirin doses vary from 75 mg daily to 500 mg daily, including 325 mg every other mg daily, including 325 mg every other dayday

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Pooled analysisPooled analysisPrimary Efficacy EndpointsPrimary Efficacy Endpoints

PHSPHS BDTBDT TPTTPT HOTHOT PPPPPP

Primary Primary Efficacy Efficacy EndpointEndpoint

CV CV DeathDeath

CV CV DeathDeath

Fatal and Fatal and nonfatal nonfatal ischemic ischemic

heart heart diseasedisease

CV CV mortality, mortality, nonfatal,nonfatal,silent MI silent MI

& & nonfatal nonfatal strokestroke

CV CV mortality, mortality, nonfatal nonfatal

MI & MI & nonfatal nonfatal strokestroke

P-valueP-valueRRRR95% CI95% CI

0.870.870.960.96

0.60-1.540.60-1.54

NSNSNANANANA

NSNSNANANANA

0.170.170.910.91

0.79-1.040.79-1.04

NSNS0.710.71

0.48-1.040.48-1.04Source: FDA’s clinical review by Dr. Juan Carlos Pelayo. NS: Not significant. NA: Not Available

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Pooled analysis Pooled analysis MI (fatal and nonfatal) (Individual studies)MI (fatal and nonfatal) (Individual studies)

StudyStudy AspirinAspirin n/N (%)n/N (%)

ControlControl n/N (%)n/N (%)

RRRR P-valueP-value 95% CI95% CI

BDTBDT 169/3429 (4.9)169/3429 (4.9) 88/1710 (5.1)88/1710 (5.1) 0.960.96 0.740.74 (0.75, 1.23)(0.75, 1.23)

HOT*HOT* 157/9399 (1.7)157/9399 (1.7) 184/9391 (2.0)184/9391 (2.0) 0.850.85 0.140.14 (0.69, 1.05)(0.69, 1.05)

PHSPHS 139/11037 (1.3)139/11037 (1.3) 239/11034 (2.2)239/11034 (2.2) 0.580.58 <0.0001<0.0001 (0.47, 0.72)(0.47, 0.72)

PPPPPP 19/2226 (0.9)19/2226 (0.9) 28/2269 (1.2)28/2269 (1.2) 0.690.69 0.210.21 (0.39, 1.23)(0.39, 1.23)

TPT*TPT* 154/2545 (6.1)154/2545 (6.1) 190/2540 (7.5)190/2540 (7.5) 0.810.81 0.040.04 (0.66, 0.99)(0.66, 0.99)

*Silent MIs included.The relative risk, p-value and 95% CI are from Mantel-Haenszel method.

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Pooled analysisPooled analysisMI (fatal and nonfatal) MI (fatal and nonfatal)

StudyStudy AspirinAspirin n/N (%)n/N (%)

ControlControl n/N (%)n/N (%)

RRRR P-P-valuevalue

95% CI95% CI

BDTBDT 169/3429 (4.9)169/3429 (4.9) 88/1710 (5.1)88/1710 (5.1)

HOT*HOT* 157/9399 (1.7)157/9399 (1.7) 184/9391 (2.0)184/9391 (2.0)

PHSPHS 139/11037 (1.3)139/11037 (1.3) 239/11034 (2.2)239/11034 (2.2)

PPPPPP 19/2226 (0.9)19/2226 (0.9) 28/2269 (1.2)28/2269 (1.2)

TPT*TPT* 154/2545 (6.1)154/2545 (6.1) 190/2540 (7.5)190/2540 (7.5)

TotalTotal## 638/28636 (2.2)638/28636 (2.2) 729/26944 (2.7)729/26944 (2.7) 0.770.77 <0.0001<0.0001 (0.69, (0.69, 0.85)0.85)

TotalTotal## (-PHS) (-PHS) 499/17599 (2.8)499/17599 (2.8) 490/15910 (3.1)490/15910 (3.1) 0.850.85 0.0110.011 (0.75, (0.75, 0.96)0.96)

TotalTotal## (-PHS-TPT)(-PHS-TPT)

345/15054 (2.3)345/15054 (2.3) 300/13370 (2.2)300/13370 (2.2) 0.880.88 0.0960.096 (0.75, (0.75, 1.02)1.02)*Silent MIs included.

#The relative risk, p-value and 95% CI are from Mantel-Haenszel method.

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Pooled analysis issuesPooled analysis issues

Some issues associated with the Some issues associated with the pooled analysispooled analysis– Why and how the 5 studies were selectedWhy and how the 5 studies were selected– Patient populations are very different among Patient populations are very different among

the 5 studiesthe 5 studies– Aspirin doses are quite differentAspirin doses are quite different

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Overall evidence for MIOverall evidence for MIMI is only a secondary endpoint in all 5 studiesMI is only a secondary endpoint in all 5 studies

Silent MI is an issueSilent MI is an issue

PHS suggested potential benefitPHS suggested potential benefit

TPT had a nominal p-value = 0.04TPT had a nominal p-value = 0.04

HOT is not clearHOT is not clear

BDT and PPP failed to show statistical BDT and PPP failed to show statistical significancesignificance

The pooled analysis did not provide any The pooled analysis did not provide any additional information beyond those provided by additional information beyond those provided by the individual studiesthe individual studies

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The new indication will expand the risk The new indication will expand the risk populationpopulation

Bleeding is one of the known adverse Bleeding is one of the known adverse events for aspirinevents for aspirin

Benefit-risk ratios should be consideredBenefit-risk ratios should be considered

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Exploratory benefit-risk analysisExploratory benefit-risk analysisMI and major bleeding (HOT)MI and major bleeding (HOT)

AspirinAspirin n/N (%)n/N (%)

PlaceboPlacebo n/N (%)n/N (%)

OverallOverall MIMI 157/9399 (1.7)157/9399 (1.7) 184/9391 (2.0)184/9391 (2.0)

BleedingBleeding 127/9399 (1.4)127/9399 (1.4) 77/9391 (0.8)77/9391 (0.8)

MaleMale MIMI 98/4962 (2.0)98/4962 (2.0) 122/4945 (2.5)122/4945 (2.5)


FemaleFemale MIMI 59/4437 (1.3)59/4437 (1.3) 62/4446 (1.4)62/4446 (1.4)


Silent MIs included.Multiple Bleeds in the same patient counted only once.

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Exploratory benefit-risk analysisExploratory benefit-risk analysis Let PLet PTT and P and PSS be the probability of MI-free in be the probability of MI-free in

aspirin group and placebo group, respectively. aspirin group and placebo group, respectively.

Let QLet QTT and Q and QSS be the probability of major bleeding be the probability of major bleeding in aspirin group and placebo group, respectively. in aspirin group and placebo group, respectively.

A possible measure of benefit-risk ratio:A possible measure of benefit-risk ratio:

R = (PR = (PTT – P – PSS) / (Q) / (QTT – Q – QSS) )

Ref: Andrew R. Willan etc. Benefit-Risk Ratios in the Assessment of Ref: Andrew R. Willan etc. Benefit-Risk Ratios in the Assessment of the Clinical Evidence of a New Therapy. Controlled Clinical Trials the Clinical Evidence of a New Therapy. Controlled Clinical Trials 1997; 18:121-1301997; 18:121-130

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Exploratory benefit-risk analysisExploratory benefit-risk analysisR measures how many MIs can be R measures how many MIs can be prevented at the cost of one major prevented at the cost of one major bleeding by using aspirin. CI can be bleeding by using aspirin. CI can be obtained as wellobtained as wellFrom the HOT study (CIs are wide)From the HOT study (CIs are wide)

Definition of major bleedings can be found in the final report of the Definition of major bleedings can be found in the final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998HOT study, THE LANCET, 1755-1762, Vol 351, 1998

RROverallOverall 0.540.54

MaleMale 0.850.85

FemaleFemale 0.140.14

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Overall, 54 MIs may be prevented at the Overall, 54 MIs may be prevented at the cost of 100 major bleeds by using aspirincost of 100 major bleeds by using aspirin

For male, 85 MIs may be prevented at the For male, 85 MIs may be prevented at the cost of 100 major bleeds by using aspirincost of 100 major bleeds by using aspirin

For female, 14 MIs may be prevented at For female, 14 MIs may be prevented at the cost of 100 major bleeds by using the cost of 100 major bleeds by using aspirinaspirin

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SummarySummaryMI is only a secondary endpoint in all 5 MI is only a secondary endpoint in all 5 studies. Silent MI is an issue studies. Silent MI is an issue For primary prevention of MI, For primary prevention of MI, – PHS suggested potential benefitPHS suggested potential benefit– TPT had a nominal p-value = 0.04TPT had a nominal p-value = 0.04– HOT failed to show statistical significance HOT failed to show statistical significance

when silent MIs were included (protocol when silent MIs were included (protocol specified)specified)

– BDT failed to show statistical significanceBDT failed to show statistical significance– PPP failed to show statistical significance PPP failed to show statistical significance

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SummarySummary

Some issues with the pooled analysisSome issues with the pooled analysis– Studies selection (how and why)Studies selection (how and why)– Risk factor of the patient population Risk factor of the patient population – Aspirin doses Aspirin doses

The pooled analysis does not provide any The pooled analysis does not provide any additional information beyond those additional information beyond those provided by the individual studiesprovided by the individual studies

The benefit and risk should be consideredThe benefit and risk should be considered

Documents

Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs