# Presentation: 942028

## Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population

- Robert T. O’Neill, Ph.D.
- Director, Office of Biostatistics
- February 18, 2005

## Issues for Discussion

- The approach we used (one of several) and why? Rofecoxib as an example - data sets available
- What do we know from the rofecoxib randomized controlled trials (RCTs)
- Data sources for projections of events to the exposed population
- Model assumptions
- A range of estimates for different scenarios
- Uncertainties in the projection strategies
- Concluding remarks

## Approach to estimation of excess eventsassociated with exposure

- Estimate the absolute difference in cumulative incidence rates of events from the VIGOR and APPROVE studies (event definitions) at monthly intervals for 1 to 36 months of exposure -  control and dose groups assumed
- Estimate from IMS data the total prescriptions (usage) for 25mg and 50 mg between years 1999 thru 2004
- Define episodes of exposure from the Caremark database and estimate approximate patient numbers with different durations of successive episodes
- Use a ratio multiplier to project up from Caremark database to IMS data base - provides U.S. estimate of number of patients with various successive episodes

## Approach to estimation of excess events associated with exposure (cont.)

- Multiply this estimate of numbers of patients with exposure episodes by the estimate of increased risk (incidence) to obtain number of excess events
- Add estimates from all mutually exclusive episode groups to get total excess events over the control background risk (rate)
- Discuss statistical  variability of estimate (confidence interval)
- Repeat for different sets of assumptions about control rates, relative risk by duration, and risk factors

## For chronically used drugs, the duration of person exposure and the calculated risk at that time matterAs does the appropriate estimate of risk and increased risk at defined intervals of time or durations of exposure

## What did we learn from two Rofecoxib clinical trials?(Studies were not prospectively designed for CV events)

| Study | VIGOR | APPROVe |
| --- | --- | --- |
| Endpoint | PUBs | Recurrent CA |
| Indication | Rheumatoid Arthritis | Polyp prevention |
| Duration | 1 year | 3 year |
| Dose | 50 mg | 25 mg |
| Mean Age  | 58 years | 59 years |
| Subjects | 79% Female | 48% Female |
| Comparator | Naproxen | Placebo |

## Replication

- Do we believe there is an effect to project?
- Is there consistency of effects in different studies on same endpoints?
- Alzheimer’s Disease
- Mild Cognitive Impairment

## Event Definitions Matter !

- Event rates are a function of event definitions and how many different subtypes are included in the definition
- Blindly adjudicated vs. investigator reported events will (can) make a difference risk estimates and risk ratios

## Event definitions in VIGOR & APPROVe We will examine two of them: 

- Confirmed thrombotic events within 14 days of last dose of study drug:
- Myocardial infarction (fatal and non-fatal), or sudden cardiac death
- 	APTC events within 14 days of last dose of study drug

## VIGORPatients withdraw from exposure (trial) early !Impact on event rates and comparisons

- Completed:
- rofecoxib:  2862 / 4047  ( 70.7% )
- naproxen: 2880 / 4029  ( 71.5% )
- Discontinued (Reasons):
- Clinical AE’s:
- 	rofecoxib:  563 (13. 9%);  naproxen: 492 (12.2%)
- Lack of efficacy:
- 	rofexocib:  256 (6.3%); naproxen: 263 (6.5%)
- Other: laboratory AE’s, moved, lost, withdrew consent

## Slide 11

## RR = 2.28, P =0.0035

**RR = 2.28, P =0.0035**
**(1.31,3.97 )**

## Myocardial infarction contributes most to the composite endpoint in the VIGOR Study

**Myocardial infarction contributes most to the composite endpoint in the VIGOR Study**

## (Huque)

## Data support risk and increased risk, increases with longer duration of exposure

**Data support risk and increased risk, increases with longer duration of exposure**

## RR = 1.92 , p = 0.008)

**RR = 1.92 , p = 0.008)**
**(1.19 , 3.11)**

## Slide 17

## Risk and increased risk, increases with exposure duration and time

- (Merck, 2005 )

**Risk and increased risk, increases with exposure duration and time**

## (Merck, 2005 )

## 25 mg Tablet strength - Increased Risk (Difference in rates) 

**25 mg Tablet strength - Increased Risk (Difference in rates)**

## 50 mg Tablet strength - Increased Risk (Difference in rates) 

**50 mg Tablet strength - Increased Risk (Difference in rates)**

## Assumptions for increased risk beyond 12 months

## Assumptions for increased risk beyond 12 months:

-  Using APPROVe estimates for 12 to 36 months

## Projections to the Population 

- 	Projections to the population involve:
- Estimating how many persons are exposed
- For how long
- To what increased risk, and
- Against what background rate

- We will rely on drug use prescription data – many assumptions are made

## National Prescription Data Sources

**IMS Health, National Prescription Audit *****Plus********* **
- Total number of prescriptions dispensed from U.S. retail pharmacies
- Does not provide patient demographic information
**IMS Health, National Disease and Therapeutic Index******
- Survey of 2000 - 3000 office-based physicians
- Projections may be unstable given small sample size

## Total number of prescriptions dispensed for Vioxx from 1999 - 2004 in outpatient settings

- IMS Health, National Prescription Audit *Plus*TM, Years 1999 – 2004, Extracted January 2005, Original File:  0501viox.dvr

## Indications for Use of Vioxx: 1999-2003

| Average use of Vioxx for 1999 - 2003 |  |
| --- | --- |
|       OA:   18% |        RA :  3% |
| Highest use was in 1999 |  |
|       OA:   23% |        RA:  5% |
| Use in 2003 |  |
|       OA:  16% |        RA:  3% |

## Estimating Patient Level Duration of Rofecoxib Exposure The Caremark DataAn attempt to estimate how many persons are exposed for how long a duration to different tablet strengths

## Source of Data for Defining Episodes of Vioxx Use

- Dataset obtained through CaremarkTM
- Large pharmacy benefits manager
- Covers 70+ million patient lives and ~25% of total U.S. prescriptions
- Dataset included all Vioxx claims (n=1,969,285) from 1 January 2002 through 31 December 2004
- Patients must have been in CaremarkTM for entire study time period (~25% of all claims)

## Analytical CaremarkTM Dataset

- We excluded prescriptions claims where:
- Strength = 12.5 mg
- Patients who were younger than 18 years
- Suspension formulation
- We also removed nonsensical data
- Days supply dispensed equal to zero
- Patients aging more than 2 years between subsequent prescriptions
- Patients whose gender changed between prescriptions
- Final dataset included 1,736,639 claims and 403,293 patients

## Limitations of CaremarkTM Data

- Not nationally representative
- Limited to insured persons with prescription drug coverage
- Under-representation of elderly persons (due to Medicare coverage)
- Poor, indigent persons underrepresented
- Quality of prescription claims data
- Data not collected for research purposes

## Definition of exposure episode

**One exposure-episode**

**Two exposure-episodes**

**Caremark  36-month window)**** **

**6/1/2002**

**Exposure-episode included in analysis**
**(****≥ 3 months observed)**

**Exposure-episode excluded (< 3 months observed)**

**1/1/2002**

**12/31/2004**

## Definition of Continuous Episode of Vioxx Use

| Days supply (initial Rx) | Time between prescriptions |
| --- | --- |
| < = 15 days | 15 days |
| 16 – 60 days | 30 days |
| 61+ days | 60 days |

## Slide 35

## Projection Ratio R IMS Rx relative increase over CaremarkTM Rx: Assume constant multiplier

- R = (Total IMS Rx’s in 1999-2004)  /(Total Rx’s in Caremark)

|  | Caremark (2002-2004) |  | IMS Rx's
(in 1,000) | R |
| --- | --- | --- | --- | --- |
|  | # Exposure
/episodes | # Rx's |  |  |
| 25 mg | 489900 | 1437231 | 84205 | 58.59 |
| 50 mg | 78748 | 190914 | 9601 | 50.29 |
| Total | 568648 | 1628145 | 93806 |  |

## What is the increased risk in exposure sub-populations?

- By dose
- By duration of exposure
- No other factors possible to examine:
- Age
- Gender
- Indication, or
- Other risk factors

## CalculationAverage Increased Number (Events) Attributable to Vioxx

- For each dose strength and length of exposure-episode L
- 		NL = (# of exposures) x (Increased Incidence) x R
- To obtain the increased events for each dose strength
- 	  Sum over all exposure lengths
- 	**	**
- 		Sum over both dose strengths to obtain total
- 	**	**

## Estimates of Population Increased Events: MI & Sudden Cardiovascular Deaths (Events) 

- 25 mg = 28,686 (95% CI upper limit = 100,159)
- 50 mg = 3,732 (9,256) – constant projection
- 	     = 4,407  (w / APPROVe Projection )
- Both 25mg and 50mg strengths combined
-     32,418 (109,415) events (w/constant projection)
- 	     33,093 (w/APPROVe Projection)

## Estimates of Population Increased Events:Confirmed thrombotic events within 14 days of last study dose

**25 mg = 41,406   (95% CI upper limit 145,046)**
**50 mg  = 6304 (15,380) for constant projection**
**	****     ****= 8034 for APPROVe projection**
** **
**Both 25mg and 50mg strengths combined**
**    ****47,710 (160,426) events for constant projection**
**	****     **
**	****     ****49,440 events for APPROVe Projection**

## Sensitivity of the Estimate

- 	Estimates of the number of increased events are influenced by:
- Validity of the assumption to use clinical trial incidence for population incidence and comparability of populations (cross trial data)
- Relevance of observational data odds ratio to short term use, hazard rate
- The Caremark inclusion criteria for left censored exposure-episode and the cutoff time of the first prescription
- The variability of the ratio projected from Caremark to US population (nationwide) and its validity
- Variability of the estimates of increased incidence
- Assumption of projection from 13-month trial exposure data to 36-month of exposure

## Where do some of the differences in estimates come from?

- Assumption of constant hazard rate calculated as events per 100 person years - can overestimate early 1 - 2 month hazard, underestimates later ( > 8 months, 1.5 year ) hazard
- Assumption of constant (proportional hazard ratio over exposure time)
- Estimate of very large number of people exposed for short (1-2 months) episodes - RCT vs. Caremark vs. Actual US pop

## Exposure Length Distribution Difference 

## Slide 44

## Slide 45

## 25 mg

- By Kaplan-Meier diff 	28,686
- By Patient-Month diff 	39,187
- 50 mg
- By Kaplan-Meier diff  	7,542 (w/APPROVe Projection)
- By Patient-Month diff	5,843
- 25 mg & 50 mg Combined
- By Kaplan-Meier diff 	36,228
- By Patient-Month diff 	45,030

## Summary

- Goal of the projection effort:
- Provide a framework for considering estimates
- Provide a range of estimates to show how assumption dependent each is - not to emphasize any one estimate
- To describe the logic, process, assumptions and uncertainties in the estimates
- To focus attention on duration of exposure and time related risk
- Given the data limitations and uncertainties, argue that there is no best approach nor estimate and it is difficult to choose an estimate without qualifying its relevance

## Acknowledgements

- ODS Team
- Laura Governale
- Gerald Dal Pan
- Aaron Mendelsohn
- Judy Staffa
- OB Team
- Joanne Zhang
- Yi Tsong
- Mohammad Huque