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![Page 1: 1 PHARM Placebo in Hypertension Adverse Reaction Meta-analysis Principals at FDA Albert DeFelice Jim Willard James Hung John Lawrence Principals at IREF.](https://reader035.fdocuments.us/reader035/viewer/2022070415/5697bfac1a28abf838c9bbbc/html5/thumbnails/1.jpg)
1
PHARM
Placebo in Hypertension Adverse Reaction Meta-analysis
Principals at FDAAlbert DeFeliceJim WillardJames HungJohn Lawrence
Principals at IREFDennis Mangano
A Collaborative Effort Effort Between:The Division of Cardio-Renal Drug Products
IREF (Ischemia Research and Education Foundation) And
Stephen Glasser
All Companies were formally contactedAnd
Formally gave permission to use the dataAnd
Agreed to retrieve & supply missing CRFs
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28 Years of Placebo-ControlledAntihypertensive Development Trials
540 Individual Protocols86,137 Randomized Patients (21,699 P, 64,438 D)
12,657 Patient Years (3,221.5 P, 9,436 D)42 Chemical Entities, 6 Drug Classes
A Blinded (from original CRFs)Meta-Analysis of (Deaths & Dropouts), by study :
9,636 Dropouts (3,056 P, 6,580 D)Mean age = 54.1 yearsMean Sitting Blood Pressure - 157.6/102.4 mm HG
Singular Primary End Point, RR (P/D) of Dropping Out
RR = 1.33 (1.28, 1.39; p<10-15)RR (Mortality, Stroke, MI) = 1.03 (0.71, 1.47; p = 0.86)
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31.9%
30.4%
33.3%
4.4%Administrative
Lack of Blood Pressure Control
Adverse Effects
Angina, MI, CHF,Stroke, TIA, Death
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Administrative OT = OTher than medical Moved, Surgery, non-compliance, etc.
Lack of Blood Pressure Control TF = Therapeutic Failure Investigator or Patient Judgment
HE = Hypertensive Emergency Diastolic BP > 110 mm Hg, increase by >10 mm Hg and/or evidence of new end organ involvement
Adverse Effects OC = Other Cardiac adverse events Angioedema, edema, low blood pressure, non-specific EKG changes
OAE = Non-cardiac, Other Adverse events Laboratory abnormalities, headache, nausea/vomiting
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All Cause Mortality Death
Non-Fatal Myocardial Infarction MI
Non-Fatal Stroke CVA
Transient Ischemic Attack TIA
Congestive Heart Failure CHF
Angina Pectoris AP
Non-Fatal Arrhythmia AR
Unscheduled Visits ER Hospitalization
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Administrative DropOuts (OT)3,081 Events (840 P, 2,241 D)*RR (placebo/Drug) = 1.09 (1.01, 1.18, p =0.031)Not a primary, 1 of many comparisons
*= Maximum Likelihood Estimation
Therapeutic Failure (TF)2,650 Events (1,266 P, 1,384 D)*RR = 2.53 (2.35, 2.73) p<10-15)Not a primary, 1 of many comparisons
Together These Two CategoriesAccount for 5,731 EventsOr 62.3% of All Drop Outs
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TF Placebo TF Drug OT Placebo OT Drug0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
3.00%
3.50%
4.00%
4.50%
5.00%
Percent of DropOut Group with ER/Hosp
ER
Hosp
22 Events Total
116 Events Total
Unscheduled Visits
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Other Adverse Events (OAE)2,734 Events (653 P, 2,081 D)*RR (placebo/Drug) = 0.87 (0.79, 0.95, p =0.0017)Not a primary, 1 of many comparisons
*= Maximum Likelihood Estimation
Other Cardiac Adverse Events (OC)469 Events (52 P, 417 D)*RR = 0.33 (0.24, 0.44) P=<10-15)Not a primary, 1 of many comparisons
Together These Two CategoriesAccount for 3,203 EventsOr 33.3% of All Drop Outs
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Other Adverse Events (OAE) Usually a combination of 2, 3 or more various kinds of signs, symptoms or laboratory abnormalities (that included skin rash, nausea and vomiting, headache, fatigue/drowsiness, etc. Rarely a single descriptor.
Other Cardiac Adverse Events (OC) Hypotension was most prominent (140 D, 8 P) with 56% being postural hypotensive phenomena, non-specific EKG changes were next most frequent, then in decreasing frequency edema of extremities, non-descript chest pain.
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TF Placebo
TF Drug
OT Placebo
OT Drug
OAE Placebo
OAE Drug
OC Placebo
OC Drug
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%Percent of DropOut Group with ER/Hosp
ER
Hosp
Unscheduled Visits
116 Events Total
222 Events Total
54 Events Total
22 Events Total
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Hypertensive Emergency (HE)279 Events (134 P, 145 D)*RR = 2.75 (2.19, 3.57) p<10-15)Not a primary, 1 of many comparisons
Meant to require new end organ damage with high blood pressureBUT
Defined as New End Organ Damage OR
Diastolic > 110 mm HgIncrease of Diastolic >10 mm Hg
Less than 25% of the 279 patients in this categoryhad clear “in words” new end organ organ involvement
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QuickTime™ and aNone decompressor
are needed to see this picture.
Baseline Cumulative Distribution Frequency
Sitting Diastolic Blood Pressure
All 9,636 drop outs (placebo & drug groups)
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QuickTime™ and aNone decompressor
are needed to see this picture.
BaselineCumulative Distribution Frequency
Supine Diastolic Blood Pressure
All 9,636 drop outs (placebo & drug groups)
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Change From BaselineCumulative Distribution Frequency
Supine Diastolic Blood Pressure
QuickTime™ and aNone decompressor
are needed to see this picture.
All 9,636 drop outs (placebo & drug groups)
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Change From BaselineCumulative Distribution Frequency
Sitting Diastolic Blood Pressure
QuickTime™ and aNone decompressor
are needed to see this picture.
All 9,636 drop outs (placebo & drug groups)
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TF Placebo
TF Drug
OT Placebo
OT Drug
OAE Placebo
OAE Drug
OC Placebo
OC Drug
HE Placebo
HE Drug
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
Percent of DropOut Group with ER/Hosp
ER
Hosp
Unscheduled Visits
22 Events Total
116 Events Total
222 Events Total
54 Events Total
52 Events Total
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TF Placebo
TF Drug
OT Placebo
OT Drug
OAE Placebo
OAE Drug
OC Placebo
OC Drug
HE Placebo
HE Drug
TIA Placebo
TIA Drug
AR Placebo
AR Drug
CHF Placebo
CHF Drug
AP Placebo
AP Drug
Death Placebo
Death Drug
MI Placebo
MI Drug
CVA Placebo
CVA Drug
0.00%
20.00%
40.00%
60.00%
80.00%
100.00%
120.00%
Proportion of Drop Out Category With ER/HOSP
ER
Hosp
7.47% of the drop out population had an unscheduled visit.
***
*= Statistically Significant RR
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Higher Risk on Treatment Higher Risk on Placebo
Relative Risk (Placebo/Drug)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
OTOAETFOCHEAPARMI
CHFDeathCVATIAVT
All dropout
ERHOSP
ER or HOSP
CVA, MI, DeathHE, AP, MI, CHF, CVA
OC, AR, Death, VT
p<10-15
p<10-16
p<10-15p<10-15
p=1.7X10-3
There were 19 different analyses performed, Inferential p of 0.001 requires p<10-6
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Favor PlaceboFavor Drug SUM-50
-40
-30
-20
-10
0
10
20
30
40
Difference (Placebo - Drug) per 1,000 Patient Years
OAE
OC
AR
Death
HE
CHF
CVA
MI
TIA
AP
RR=2.75
p=<10-15
RR=0.87p=0.0017
RR=0.33
p<10-15
RR=0.89p=0.001
All Drop Outs Without OT and TFSUM
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Favor PlaceboFavor Drug SUM-50
-40
-30
-20
-10
0
10
Difference (Placebo - Drug) per 1,000 Patient Years
OAE
OC
AR
Death
CHF
CVA
MI
TIA
AP
RR=0.80
p<10-8
RR=0.87p=0.017
RR=0.33
p<10-15
All Drop Outs Without OT, TF and HE
SUM
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Favor PlaceboFavor Drug SUM-0.5
0
0.5
1
1.5
2
Difference per 1,000 patient years
Death
MI
CVA
Irreversible Harm
RR = 1.03p = 0.86 Sum
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All Cause Mortality11 trials + HVET Pilot + PHARM179,766 patient years of follow-upVAH-NIH had no systolic pressurereported
Solid Colors = PlaceboStippled = Drug Treated
Points to PHARM
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Non-Fatal Stroke
Solid Colors = Placebo
Stippled = Drug Treated
11 trials + PHARM178,334 patient years of follow-up
Points to PHARM
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Non-Fatal MISolid Colors = PlaceboStippled = Drug Treated
11 trials + PHARM178,334 patient years of follow-up
Points to PHARM
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All Cause Mortality11 trials + PHARM + HVET-pilot Solid Colors = Placebo
Stippled = Drug Treated
Points to PHARM
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Non-Fatal Stroke11 trials + PHARM (HVET-pilot had onlyMortality)
Solid Colors = PlaceboStippled = Drug Treated
Points to PHARM
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11 trials + PHARM (HVET-pilot hadonly Mortality)
Non-Fatal MISolid Colors = PlaceboStippled = Drug Treated
Points to PHARM
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28Lewington et al Lancet 360:1903-1913, 20002
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29Collins & MacMahon Brit Med Bul 50:272-298, 1994
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So, Where Does That Leave Us?In My Opinion:
30 years and 590 trials (12,657 patient years)have produced no evidence that there is an increase of irreversible harm produced by the utilization of placebo in short-termtrials
The population represented by PHARM appears to be like that of all publishedstudies, but of relatively low absolute risk(low systolic blood pressure and low chronological age)
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Equipoise can be maintained (mainly because of the low absolute risk), suchtrials can continue; after another 30 to 50 years, one should check on the wisdom of continued equipoise
The only meaningful discussion shouldrelate to could these trials be made “safer” by limiting chronological age toSome arbitrary limit (say 50), and systolicBlood pressure to some arbitrary limit(say 145)
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Back-up Stuff, unorganized
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AP AR CVA CHF Death HE MI OT OAE OC TF TIA VT-15
-10
-5
0
5
10
15
-15
-10
-5
0
5
10
15
Change From Baseline (mm Hg) for Event Group
Difference (Drug-Placeebo) for the group (mm Hg)
Drop Out Category
Change (Base-Last) for Group
Diff (Drug - Placebo)
Sitting Diastolic Blood Pressure
* *
*
*
*
*
*
*
*
*
*
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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63
By Patient Summary Entire SessionsAll Measurements in a Session, 24 or more Hours
Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug
Placebo Drug
-12
-10
-8
-6
-4
-2
0
2
Treatment Effect (Treatment - Baseline) mm Hg
Sys
Dia
Sys Dia
p < 0. 000000000
p < 0. 000000000
p = 0. 6
1st Analysis, not to be trusted
p = 0. 5
p values are that Difference
is = 0
May 1999From 12/98
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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63
Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug
Morning By Patient Summary6:00 A.M. to 9:59 A.M.
Placebo Drug
-12
-10
-8
-6
-4
-2
0
2
Drug Effect (Treatment - Baseline) mm Hg
Sys
Dia
SysDia
p < 0. 000000000
p < 0. 000000000
p = 0. 9
1st Analysis, not to be trusted
p = 0. 6
p values are that Difference
is = 0
Value = -0.05
May 1999From 12/98
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Placebo Drug
-14
-12
-10
-8
-6
-4
-2
0
2
Treatment Effect (Treatment - Baseline) mm Hg
Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63
Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug
DayTime By Patient Treatment Effect10:00 A.M. to 5:59 P.M.
Sys
Dia
Sys Dia
p < 0. 000000000
p < 0. 000000000
1st Analysis, not to be trusted
p = 0. 6
p values are that Difference
is = 0
p = 0. 3
May 1999From 12/98
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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63
By Patient Summary Entire SessionsAll Measurements in a Session, 24 or more Hours
Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug
Placebo Drug
-12
-10
-8
-6
-4
-2
0
2
Treatment Effect (Treatment - Baseline) mm Hg
Sys
Dia
Sys Dia
p < 0. 000000000
p < 0. 000000000
p = 0. 6
1st Analysis, not to be trusted
p = 0. 5
p values are that Difference
is = 0
May 1999From 12/98
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diastolic systolic
-14
-12
-10
-8
-6
-4
-2
0
2Mean Change From Baseline (mm Hg)
placebo abp
Rx abp
placebo cuff
RX Cuff
Preliminary Results from 9 Trialsn = about700 for cuff, 250 for abpm
SE
May 1999From 12/98
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closest 5 min 10 min 30 min 60 min 120 min60
70
80
90
100
110
120
130
140
150
160
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Standing Systolic
abp Systolic
Standing Diastolic
abp Diastolic
Correlation Systolic
Correlation Diastolic
Blo
od P
ress
ure
(m
m H
g)C
orrelation C
oefficient
Simultanious (?) ABPM and Cuff Blood Pressures
May 1999From 12/98