Placebo in Hypertension Adverse Reaction Meta-analysis
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Placebo in Hypertension Adverse Reaction Meta-analysis PHARM A Collaborative Effort Effort Between: The Division of Cardio-Renal Drug Products IREF (Ischemia Research and Education Foundation) And Stephen Glasser Principals at FDA Albert DeFelice Jim Willard James Hung John Lawrence

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Placebo in Hypertension Adverse Reaction Meta-analysis

PHARM

A Collaborative Effort Effort Between:

The Division of Cardio-Renal Drug Products

IREF (Ischemia Research and Education Foundation)

And

Stephen Glasser

Principals at FDA

Albert DeFelice

Jim Willard

James Hung

John Lawrence

Principals at IREF

Dennis Mangano

All Companies were formally contacted

And

Formally gave permission to use the data

And

Agreed to retrieve & supply missing CRFs


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A Blinded (from original CRFs)

Meta-Analysis of (Deaths & Dropouts), by study :

28 Years of Placebo-Controlled

Antihypertensive Development Trials

540 Individual Protocols

86,137 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

9,636 Dropouts (3,056 P, 6,580 D)

Mean age = 54.1 years

Mean 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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Angina, MI, CHF,

Stroke, TIA, Death

4.4%

Administrative

Adverse Effects

31.9%

33.3%

30.4%

Lack of Blood Pressure Control


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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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= Maximum Likelihood Estimation

*

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

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 Categories

Account for 5,731 Events

Or 62.3% of All Drop Outs


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116 Events

Total

5.00%

Hosp

4.50%

ER

4.00%

3.50%

3.00%

Percent of DropOut Group with ER/Hosp

2.50%

22 Events

Total

2.00%

1.50%

1.00%

0.50%

0.00%

TF Placebo

TF Drug

OT Placebo

OT Drug

Unscheduled Visits


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= Maximum Likelihood Estimation

*

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

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 Categories

Account for 3,203 Events

Or 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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14.00%

Hosp

12.00%

ER

10.00%

8.00%

Percent of DropOut Group with ER/Hosp

6.00%

4.00%

2.00%

0.00%

TF Drug

OT Drug

OC Drug

OAE Drug

TF Placebo

OC Placebo

OT Placebo

OAE Placebo

Unscheduled Visits

54 Events

Total

222 Events

Total

116 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

Less than 25% of the 279 patients in this category

had clear “in words” new end organ organ involvement

Meant to require new end organ damage with high blood pressure

BUT

Defined as New End Organ Damage

OR

Diastolic > 110 mm Hg

Increase of Diastolic >10 mm Hg


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Baseline

Cumulative Distribution Frequency

Sitting Diastolic Blood Pressure

All 9,636 drop outs (placebo & drug groups)


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Baseline

Cumulative Distribution Frequency

Supine Diastolic Blood Pressure

All 9,636 drop outs (placebo & drug groups)


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Change From Baseline

Cumulative Distribution Frequency

Supine Diastolic Blood Pressure

All 9,636 drop outs (placebo & drug groups)


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Change From Baseline

Cumulative Distribution Frequency

Sitting Diastolic Blood Pressure

All 9,636 drop outs (placebo & drug groups)


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25.00%

Hosp

ER

20.00%

15.00%

Percent of DropOut Group with ER/Hosp

10.00%

5.00%

0.00%

TF Drug

OT Drug

OC Drug

HE Drug

OAE Drug

TF Placebo

OT Placebo

HE Placebo

OC Placebo

OAE Placebo

Unscheduled Visits

52 Events

Total

54 Events

Total

222 Events

Total

116 Events

Total

22 Events

Total


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7.47% of the drop out population had an unscheduled visit.

120.00%

Hosp

100.00%

ER

80.00%

Proportion of Drop Out Category With ER/HOSP

60.00%

40.00%

*

20.00%

*

*

0.00%

MI Drug

TF Drug

OT Drug

OC Drug

HE Drug

AR Drug

AP Drug

TIA Drug

CHF Drug

CVA Drug

OAE Drug

MI Placebo

HE Placebo

Death Drug

TF Placebo

AR Placebo

OT Placebo

AP Placebo

OC Placebo

TIA Placebo

CVA Placebo

CHF Placebo

OAE Placebo

Death Placebo

= Statistically Significant RR

*


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There were 19 different analyses performed, Inferential p of 0.001 requires p<10-6

Relative Risk (Placebo/Drug)

OT

p=1.7X10-3

OAE

p<10-15

TF

p<10-15

OC

p<10-15

HE

AP

AR

MI

CHF

Death

CVA

TIA

VT

p<10-16

All dropout

ER

HOSP

ER or HOSP

CVA, MI, Death

HE, AP, MI, CHF, CVA

OC, AR, Death, VT

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Higher Risk on Treatment Higher Risk on Placebo


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All Drop Outs Without OT and TF 0.001 requires p<10

40

SUM

30

AP

20

TIA

RR=2.75

-15

p=<10

MI

10

CVA

0

Difference (Placebo - Drug) per 1,000 Patient Years

CHF

RR=0.87

-10

HE

p=0.0017

Death

-20

RR=0.89

p=0.001

AR

RR=0.33

-30

-15

p<10

OC

-40

OAE

-50

Favor Placebo

Favor Drug

SUM


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All Drop Outs Without OT, TF and HE 0.001 requires p<10

10

SUM

0

AP

RR=0.87

TIA

p=0.017

-10

MI

RR=0.80

-8

p<10

CVA

Difference (Placebo - Drug) per 1,000 Patient Years

-20

CHF

RR=0.33

Death

-15

p<10

-30

AR

OC

-40

OAE

-50

Favor Placebo

Favor Drug

SUM


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Irreversible Harm 0.001 requires p<10

2

RR = 1.03

1.5

Sum

p = 0.86

CVA

1

Difference per 1,000 patient years

MI

0.5

Death

0

-0.5

Favor Placebo

Favor Drug

SUM




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So, Where Does That Leave Us? 0.001 requires p<10

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-term

trials

The population represented by PHARM

appears to be like that of all published

studies, but of relatively low absolute risk

(low systolic blood pressure and low

chronological age)


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Equipoise can be maintained (mainly 0.001 requires p<10

because of the low absolute risk), such

trials can continue; after another 30 to

50 years, one should check on the

wisdom of continued equipoise

The only meaningful discussion should

relate to could these trials be made

“safer” by limiting chronological age to

Some arbitrary limit (say 50), and systolic

Blood pressure to some arbitrary limit

(say 145)


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Back-up Stuff, unorganized 0.001 requires p<10


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Sitting Diastolic Blood Pressure 0.001 requires p<10

15

15

Change (Base-Last) for Group

*

Diff (Drug - Placebo)

10

10

5

5

*

Change From Baseline (mm Hg) for Event Group

Difference (Drug-Placeebo) for the group (mm Hg)

0

0

*

*

-5

-5

*

*

*

*

*

*

-10

-10

*

-15

-15

AP

AR

CVA

CHF

Death

HE

MI

OT

OAE

OC

TF

TIA

VT

Drop Out Category


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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 0.001 requires p<10

By Patient Summary Entire Sessions

All 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

2

0

Dia

Sys

p = 0. 5

p = 0. 6

-2

-4

-6

Treatment Effect (Treatment - Baseline) mm Hg

Dia

-8

p < 0. 000000000

-10

p values are that Difference

is = 0

Sys

-12

p < 0. 000000000

1st Analysis, not to be trusted

May 1999

From 12/98


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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 0.001 requires p<10

Morning By Patient Summary

6:00 A.M. to 9:59 A.M.

Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug

Placebo

Drug

2

0

Dia

Sys

p = 0. 6

Value = -0.05

-2

p = 0. 9

-4

-6

Drug Effect (Treatment - Baseline) mm Hg

Dia

p < 0. 000000000

-8

-10

p values are that Difference

Sys

is = 0

p < 0. 000000000

-12

1st Analysis, not to be trusted

May 1999

From 12/98


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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 0.001 requires p<10

DayTime By Patient Treatment Effect

10:00 A.M. to 5:59 P.M.

Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug

Placebo

Drug

2

0

Sys

Dia

p = 0. 3

p = 0. 6

-2

-4

-6

Treatment Effect (Treatment - Baseline) mm Hg

-8

Dia

p < 0. 000000000

-10

-12

p values are that Difference

Sys

is = 0

p < 0. 000000000

-14

1st Analysis, not to be trusted

May 1999

From 12/98


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Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 0.001 requires p<10

By Patient Summary Entire Sessions

All 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

2

0

Dia

Sys

p = 0. 5

p = 0. 6

-2

-4

-6

Treatment Effect (Treatment - Baseline) mm Hg

Dia

-8

p < 0. 000000000

-10

p values are that Difference

is = 0

Sys

-12

p < 0. 000000000

1st Analysis, not to be trusted

May 1999

From 12/98


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Preliminary Results from 9 Trials 0.001 requires p<10

n = about700 for cuff, 250 for abpm

diastolic

systolic

2

0

SE

-2

-4

-6

Mean Change From Baseline (mm Hg)

-8

-10

-12

-14

placeboabp

placebocuff

Rx abp

RX Cuff

May 1999

From 12/98


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160 0.001 requires p<10

2

150

1.8

140

1.6

130

1.4

120

1.2

Correlation Coefficient

Blood Pressure (mm Hg)

110

1

100

0.8

90

0.6

80

0.4

70

0.2

60

0

5 min

10 min

30 min

60 min

120 min

closest

Standing Systolic

abp Systolic

Correlation Systolic

Standing Diastolic

Correlation Diastolic

abp Diastolic

Simultanious (?) ABPM and Cuff Blood Pressures

May 1999

From 12/98


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