chenxiong (charles) le, ph.d. obi/ob/opass/cder, fda cardiovascular and renal drugs
DESCRIPTION
Issues with the statistical analyses in the citizen’s petition for aspirin on reduction of the risk of 1 st MI. Chenxiong (Charles) Le, Ph.D. OBI/OB/OPaSS/CDER, FDA Cardiovascular and Renal Drugs Advisory Committee Meeting December 8, 2003. Outline. Background - PowerPoint PPT PresentationTRANSCRIPT
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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BackgroundBackground
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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BackgroundBackground
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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BackgroundBackground
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
AspirinAspirin ControlControlnn NN nn NN
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
AspirinAspirin ControlControlnn NN nn NN
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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Exploratory benefit-risk analysisExploratory benefit-risk analysis
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)
BleedingBleeding 80/4962 (1.6)80/4962 (1.6) 51/4945 (1.0)51/4945 (1.0)
FemaleFemale MIMI 59/4437 (1.3)59/4437 (1.3) 62/4446 (1.4)62/4446 (1.4)
BleedingBleeding 47/4437 (1.1)47/4437 (1.1) 26/4446 (0.6)26/4446 (0.6)
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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Exploratory benefit-risk analysisExploratory benefit-risk analysis
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