# Presentation: 265574

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

- Chenxiong (Charles) Le, Ph.D.
- OBI/OB/OPaSS/CDER, FDA
- Cardiovascular and Renal Drugs
- Advisory Committee Meeting
-  December 8, 2003

## Outline

- Background
- Sponsor’s ‘meta-analysis’
- HOT study issues
- Pooled analysis issues
- Exploratory benefit-risk analysis
- Summary

## Background

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

## Background

- Five studies
- (BDT) British Doctor’s Trial (N=5139)
- (PHS) Physician’s Health Study (N=22071)
- (TPT) Thrombosis Prevention Trial (N=5085)
- (HOT) Hypertension Optimal Treatment Study (N=18790)
- (PPP) Primary Prevention Project (N=4495)
- Total # of subjects = 55580

## Background

-  The agency considered aspirin (BDT and PHS) for this indication before and did not approve it
- PHS showed that some patients had a prior MI and aspirin is already known to reduce the risk of recurrent MI
- PHS did not achieve statistical significance when all deaths as well as nonfatal MI and stroke were combined
- BDT, despite its similarity to PHS, was neutral on the effect of aspirin on MI

## Background

- What is new in this petition?
- Three new studies (TPT, HOT, PPP) were included
- HOT (N = 18790) is the largest among the three studies (TPT, N = 5085, PPP, N = 4495)
- Sponsor’s ‘Meta-analysis’ of the five studies was submitted to support the petition

## Sponsor’s ‘meta-analysis’

**Nonfatal MI **

|  | Aspirin |  | Control |  |
| --- | --- | --- | --- | --- |
|  | n | N | n | N |
| PHS | 129 | 11037 | 213 | 11034 |
| BDT | 80 | 3429 | 41 | 1710 |
| TPT | 94 | 2545 | 137 | 2540 |
| HOT | ... | ... | ... | ... |
| PPP | 15 | 2226 | 22 | 2269 |
| Total | 318 | 19237 | 413 | 17553 |
| RR 
(95%CI) | 0.68
(0.59-0.79) |  |  |  |

## Sponsor’s ‘meta-analysis’

**Composite of MI, stroke and CV death**

|  | Aspirin |  | Control |  |
| --- | --- | --- | --- | --- |
|  | n | N | n | N |
| PHS | 307 | 11037 | 370 | 11034 |
| BDT | 289 | 3429 | 147 | 1710 |
| TPT | 228 | 2545 | 260 | 2540 |
| HOT | 315 | 9399 | 368 | 9391 |
| PPP | 47 | 2226 | 71 | 2269 |
| Total | 1186 | 28636 | 1216 | 26944 |
| RR (95%CI) | 0.85
(0.79-0.93) |  |  |  |

## Sponsor’s ‘meta-analysis’

**Cardiovascular death**

|  | Aspirin |  | Control |  |
| --- | --- | --- | --- | --- |
|  | n | N | n | N |
| PHS | 81 | 11037 | 83 | 11034 |
| BDT | 148 | 3429 | 79 | 1710 |
| TPT | 101 | 2545 | 81 | 2540 |
| HOT | 133 | 9399 | 140 | 9391 |
| PPP | 17 | 2226 | 31 | 2269 |
| Total | 480 | 28636 | 414 | 26944 |
| RR (95%CI) | 0.98
(0.85-1.12) |  |  |  |

## The HOT study 

- Silent MI matters
- Primary endpoint was major CV events (non-fatal and **silent MI**, non-fatal stroke, and cardiovascular death)
- Silent MIs were obtained by comparing the ECGs at baseline and final visit
- n=9399 in aspirin and n=9391 in placebo

## The HOT study

- Silent MI matters
- There were 48% and 31% silent MIs in the aspirin group and placebo group, respectively

|  | Aspirin
n (%) | Placebo
n (%) |
| --- | --- | --- |
| Silent MI | 75  (48) | 57  (31) |
| Other MI | 82  (52) | 127 (69) |
| Total MI | 157  | 184 |

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

## The HOT study 

- Silent MI matters

| 
Endpoint | Aspirin
N=9399
n (%) | Placebo
N=9391
n (%) | P-Value | RR
(95% CI) |
| --- | --- | --- | --- | --- |
| Major CV events  | 388 (4.1) | 425 (4.5) | 0.17 | 0.91 (0.79-1.04) |
| Major CV events (- Silent MI) | 315 (3.4) | 368 (3.9) | 0.03 | 0.85 (0.73-0.99) |
| All MI  | 157 (1.7) | 184 (2.0) | 0.13 | 0.85 (0.69-1.05) |
| All MI (- Silent MI ) | 82 (0.9) | 127 (1.4) | 0.002 | 0.64 (0.49-0.85) |
| All Stroke | 146 (1.6) | 148 (1.6) | 0.88 | 0.98 (0.78-1.24) |
| CV Mortality | 133 (1.4) | 140 (1.5) | 0.65 | 0.95 (0.75-1.20) |
| Total Mortality | 284 (3.0) | 305 (3.2) | 0.36 | 0.93 (0.79-1.09) |

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

## The HOT study issues

- The published paper reported that statistical significance was achieved for the composite endpoint of non-fatal MI, non-fatal stroke, and CV death, and for MI alone.  This is misleading
- Silent MIs should be included in both efficacy endpoints according to the study protocol
**When silent MIs are included, both the primary endpoint (non-fatal & silent MI, non-fatal stroke, and CV death) and MI alone are not statistically significant**

## Pooled analysis 

- Studies’ summary

|  | PHS | BDT | TPT | HOT | PPP |
| --- | --- | --- | --- | --- | --- |
| Total N | 22071 | 5139 | 5085 | 18790 | 4495 |
| Ave. Followup | 2.5 | ? | ? | 3.8 | 3.6 |
| Patient Population | Healthy male MD | Healthy male MD | Male at high risk of CVD | Pts /DBP from 100-115 mmHg | Pts / one or more CV risk factor |
| Age Range | 40-84 | 50-78 | 45-69 | 50-80 | 50-80+ |
| Female | 0 | 0 | 0 | 8883/47.3 | 1912/42.5 |
| Dose | 325 mg QOD | 500 mg QD | 75 mg QD | 75 mg QD | 100 mg QD |

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

## Pooled analysis

- The patient populations were quite different among the 5 studies (ranging from apparently healthy physicians to patients at high risk of CV disease)
- Aspirin doses vary from 75 mg daily to 500 mg daily, including 325 mg every other day

## Pooled analysis

- Primary Efficacy Endpoints

|  | PHS | BDT | TPT | HOT | PPP |
| --- | --- | --- | --- | --- | --- |
| Primary Efficacy Endpoint

 | CV 
Death

 | CV Death

 | Fatal and nonfatal ischemic heart disease | CV mortality, nonfatal,
silent MI & nonfatal stroke | CV mortality, nonfatal MI & nonfatal stroke |
| 
P-value
RR
95% CI | 
0.87
0.96
0.60-1.54 | 
NS
NA
NA | 
NS
NA
NA | 
0.17
0.91
0.79-1.04 | 
NS
0.71
0.48-1.04 |

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

## Pooled analysis 

- MI (fatal and nonfatal) (Individual studies)

| Study | Aspirin
 n/N (%) | Control
 n/N (%) | RR | P-value | 95% CI |
| --- | --- | --- | --- | --- | --- |
| BDT | 169/3429   (4.9) | 88/1710     (5.1) | 0.96 | 0.74 | (0.75, 1.23) |
| HOT* | 157/9399   (1.7) | 184/9391   (2.0) | 0.85 | 0.14 | (0.69, 1.05) |
| PHS | 139/11037 (1.3) | 239/11034 (2.2) | 0.58 | <0.0001 | (0.47, 0.72) |
| PPP | 19/2226     (0.9) | 28/2269     (1.2) | 0.69 | 0.21 | (0.39, 1.23) |
| TPT* | 154/2545   (6.1) | 190/2540   (7.5) | 0.81 | 0.04 | (0.66, 0.99) |

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

## Pooled analysis

- MI (fatal and nonfatal)

| Study |       Aspirin
      n/N (%) |       Control
      n/N (%) | RR | P-value | 95% CI |
| --- | --- | --- | --- | --- | --- |
| BDT | 169/3429   (4.9) | 88/1710     (5.1) |  |  |  |
| HOT* | 157/9399   (1.7) | 184/9391   (2.0) |  |  |  |
| PHS | 139/11037 (1.3) | 239/11034 (2.2) |  |  |  |
| PPP | 19/2226     (0.9) | 28/2269     (1.2) |  |  |  |
| TPT* | 154/2545   (6.1) | 190/2540   (7.5) |  |  |  |
| Total# | 638/28636 (2.2) | 729/26944 (2.7) | 0.77 | <0.0001 | (0.69, 0.85) |
| Total# (-PHS) | 499/17599 (2.8) | 490/15910 (3.1) | 0.85 | 0.011 | (0.75, 0.96) |
| Total# 
(-PHS-TPT) | 345/15054 (2.3) | 300/13370 (2.2) | 0.88 | 0.096 | (0.75, 1.02) |

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

## Pooled analysis issues

**Some issues associated with the pooled analysis**
- Why and how the 5 studies were selected
- Patient populations are very different among the 5 studies
- Aspirin doses are quite different

## Overall evidence for MI

- MI is only a secondary endpoint in all 5 studies
-     Silent MI is an issue
- PHS suggested potential benefit
- TPT had a nominal p-value = 0.04
- HOT is not clear
- BDT and PPP failed to show statistical significance
- The pooled analysis did not provide any additional information beyond those provided by the individual studies

## Exploratory benefit-risk analysis

- The new indication will expand the risk population
- Bleeding is one of the known adverse events for aspirin
- Benefit-risk ratios should be considered

## Exploratory benefit-risk analysis

- MI and major bleeding (HOT)

|  |  | Aspirin
  n/N       (%) | Placebo
   n/N      (%) |
| --- | --- | --- | --- |
| Overall | MI | 157/9399 (1.7) | 184/9391 (2.0) |
|  | Bleeding | 127/9399 (1.4) | 77/9391   (0.8) |
| Male | MI | 98/4962   (2.0) | 122/4945 (2.5) |
|  | Bleeding | 80/4962   (1.6) |  51/4945  (1.0) |
| Female | MI | 59/4437   (1.3) | 62/4446   (1.4) |
|  | Bleeding | 47/4437   (1.1) | 26/4446   (0.6) |

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

## Exploratory benefit-risk analysis

-     Let PT  and PS be the probability of MI-free in aspirin group and placebo group, respectively.
-    Let QT and QS be the probability of major bleeding in aspirin group and placebo group, respectively.
-    A possible measure of benefit-risk ratio:
-    		R = (PT – PS) / (QT – QS)
- 	Ref: Andrew R. Willan etc. Benefit-Risk Ratios in the Assessment of the Clinical Evidence of a New Therapy.  Controlled Clinical Trials 1997; 18:121-130

## Exploratory benefit-risk analysis

- R measures how many MIs can be prevented at the cost of one major bleeding by using aspirin.   CI can be obtained as well
- From the HOT study (CIs are wide)
- 	Definition of major bleedings can be found in the final report of the HOT study, THE LANCET, 1755-1762, Vol 351, 1998

|  | R |
| --- | --- |
| Overall | 0.54 |
| Male | 0.85 |
| Female | 0.14 |

## Exploratory benefit-risk analysis

- Overall, 54 MIs may be prevented at the cost of 100 major bleeds by using aspirin
- For male, 85 MIs may be prevented at the cost of 100 major bleeds by using aspirin
- For female, 14 MIs may be prevented at the cost of 100 major bleeds by using aspirin

## Summary

- MI is only a secondary endpoint in all 5 studies.  Silent MI is an issue
- For primary prevention of MI,
**PHS suggested potential benefit**
- TPT had a nominal p-value = 0.04
- HOT failed to show statistical significance when silent MIs were included (protocol specified)
**BDT failed to show statistical significance**
- PPP failed to show statistical significance

## Summary

- Some issues with the pooled analysis
- Studies selection (how and why)
- Risk factor of the patient population
- Aspirin doses
- The pooled analysis does not provide any additional information beyond those provided by the individual studies
- The benefit and risk should be considered