# Presentation: 102542

## Phenylpropanolamine & Risk of Hemorrhagic Stroke

**Lois La Grenade, M.D., M.P.H.**
**Office of Postmarketing Drug Risk Assessment**
**Center for Drug Evaluation and Research**
**Food and Drug Administration**

## Plan

**Historical Background**
**Case Reviews**
**Review HSP/Yale Study**
**Highlight important aspects**
**Address CHPA’s concerns**
**Summarize results**
**Assess Public Health Impact**
**Overall Conclusions**

## Background

**Pre 1984: Case reports of PPA & hemorrhagic stroke**
**1984: O’Neill and Van de Carr’s case-control study**
**Medicaid data - Michigan & Minnesota**** **
**1991: Review of FDA’s spontaneous reporting system (SRS 1969-1991)**
**1991 -2000: Continued receipt of hemorrhagic stroke case reports**

## Background 1984

**O’Neill and Van de Carr 1984 **
**association between PPA & hemorrhagic stroke, compared with other adrenergic decongestants**
**Study Limitations**
**retrospective study, automated databases**
**Rx only (not OTC)**
**60-day exposure window**
**misclassification**

## Background 1991: ADRs reported with CVA 

## Background 1991

**1991 SRS Review**
**1969 - Jan 1991**
**29 US cases CVA, 22 hemorrhagic stroke**
**16 (73%) appetite suppressant**
**6 (27%) cough/cold preparation**
**Young age (median 27, 35); female gender**
**55% occurred with first use of PPA**

## Background 1991

**	****	****	****         ****Hypothesis: **
**	****PPA containing products (appetite suppressant & cough/cold), especially first use, are associated with an increased risk of hemorrhagic stroke in young women **

## Case Review 2000

**2000 AERS Review**
**Feb 1, 1991 - Jul 17, 2000**
**22 US cases, 4 deaths (all female)**
**19 (86%) cough/cold preparations**
**3 (14%) appetite suppressants**
**Females 18 (86%) **
**Median age 35 years**

## Case Review 2000

**Median time to onset after last dose = 4 hours**
**Median duration of use = 24 hours **
**82% of events **_**<**_** 3 days of PPA use**
**All cases occurred with preparations containing 75 mg (sustained release)**
**Shift in demographics - more cough/cold users**
**    ****but median age same (35 years)**

## Typical Case Report

**Young person, otherwise healthy**
**Develops cough/cold/ ”flu”**
**Takes PPA product**
**Within a few days, with no warning develops catastrophic event - hemorrhagic stroke**
**Hospitalized **
**Permanently disabled or dies**

## Underreporting of Cases

**Substantial underreporting for Rx drugs, possibly as low as 1%**
**No legal requirement for manufacturers to report non-monograph drug adverse events**
**No learned intermediary who is aware of the PPA exposure**
**Underreporting for OTC products >> Rx products**

## The Hemorrhagic Stroke Project (HSP)

**Phenylpropanolamine & Risk of Hemorrhagic Stroke**
**Sponsored by CHPA, designed & conducted by Yale**
**Protocol reviewed by Yale, CHPA & FDA**
**Designed to test hypotheses generated by FDA 1991, 1984 reviews**

## HSP Case-control Study - PPA & Hemorrhagic Stroke

**Objectives**
**1. Among men and women aged 18 – 49 years, to estimate the association between PPA   and hemorrhagic stroke generally, and**
**2. by type of PPA exposure**

## Objectives contd.

**3. Among women aged 18-49 years to estimate **
**(a) the association between first use of PPA and hemorrhagic stroke and **
**(b) PPA in appetite suppressants and**
**     ****hemorrhagic stroke.**
**   ****Most important from FDA viewpoint as **
**this was generated from our reviews**
**	**

## Study Design

**Case-control method - suited to rare events such as hemorrhagic stroke in young people**
**Captures all cases in a specified time-period**
**Results available more quickly than with cohort studies**
**Less expensive**

## Design Strengths

**Targeted to test specific hypotheses**
**Prospective**
**Carefully designed to minimize bias**
**Conducted with great attention to detail**
**Careful analysis**
**Internal consistency shown across the various strata that were analyzed**
**Largest hemorrhagic stroke study to date **

## Design Limitations

**Sample size & power borderline**
**Powered to detect OR of 5 or greater**
**for practical, not scientific/public health considerations**
**Study duration was 5+ years**

## Small Sample Size (CHPA)

**Low statistical power**
**May be subject to exposure misclassification**
**May introduce important biases**
**Results may not be robust**

## Small Sample Size (FDA)

**Largest study ever of hemorrhagic stroke **
**Low power reduces probability of showing a difference if one exists **
** ****major difference observed despite low power**
**Bias is a product of poor study design/conduct **
**HSP well designed, internal safeguards, QA**
**Internal consistency in subset analyses underscores robustness of data**

## Potential Confounders

**Aphasia**
**Smoking**
**Hypertension**
**Race**
**Education**
**Each adjusted for in analysis**
**Not necessary to match for all - too long, too complex**

## Odds Ratios for Hemorrhagic Stroke with PPA Use in Subjects  without Hypertension & without Aphasia

## Misclassification (CHPA)

**Errors in classification could skew results**
**    ****-participant recall**
**   ****-product identification**

## Misclassification (FDA)

**Subjects blinded to exposure of interest**
**Structured interview & exposure verification process**
**Recall bias minimized by short interval between event & interview for both cases & controls**
**No data suggesting differential misclassification that would generate spurious association**
**Misclassification typically biases OR towards 1**

## Surrogate Responders (CHPA)

**Exclusion of fatal & severely aphasic cases was inappropriate**
**Excluded cases could differ in their exposure to PPA & other risk factors**
**Analysis based on survivors may introduce survival bias**

## Surrogate Responders (FDA)

**Modest use of surrogate responders would introduce overwhelming misclassification error**
**verified by FDA & HSP investigators in planning stage, and agreed to by CHPA**
**would remove all possibility of detecting an association between PPA and hemorrhagic stroke**

## Surrogate Responders (FDA) contd

**Aphasic subjects may underreport PPA exposure (given the increased OR for non-aphasic subjects)**
**No data to suggest that PPA exposure is related to the severity of the stroke **
**Several epidemiologic studies show that use of surrogate interviews is a major source of bias* **
***Armstrong, White & Saracci, 1992**

## FDA Analyses

**Confirmed the major findings by conducting its own analyses on data submitted by Yale**
**Explored dose response relationship**
**Conducted sensitivity analyses to examine sparse data bias due to small sample size**

## HSP Study Results

**The Yale study supported an increased risk of hemorrhagic stroke associated with PPA use. **
**Findings were statistically significant among appetite suppressant users and first day users of PPA as a cough/cold remedy.**

## Public Health Impact

**Attributable Risk*:**
**1. How much of a disease that occurs can be attributed to a certain exposure?**
**2. How much of the risk (incidence) of disease can we hope to prevent if we are able to eliminate exposure to the agent in question?**
***Gordis, 1996**

## Total Number of PPA dose units sold annually by OTC status

**	****	****	****1995     1996     1997     1998     1999**
**Total            8.8       8.4         6.0         6.2        6.0**
**OTC            6.8       6.6         6.0         4.7        4.5**
**Non-OTC   2.0        1.8         1.6        1.5        1.5**
**Numbers in billions**
*******IMS HEALTH, Retail & Provider PerspectiveTM**

## Total Number PPA dose units sold annually by indication*

**	****	****         ****1995    1996   1997   1998   1999**
**Total         8.8       8.4      6.0      6.2      6.0**
**C/C (%)    97        98       98        98       98**
**Diet (%)    3          2          2         2          2**
**Numbers in billions**
*******IMS HEALTH, Retail & Provider PerspectiveTM**

## Public Health Impact

**Study population similar to US population **
**Whites slightly overrepresented in study population**
**Blacks & Hispanics slightly underrepresented**
**Therefore study results generalizable to US population.**

## Public Health Impact

**Study results projected to US population to estimate public health impact**
**Summary of study results**
**Total # hemorrhagic strokes 1714**
**Total cases 702**
**8 cases:  1st use PPA cough/cold remedy**
**6 cases:  PPA appetite suppressant**

## Public Health Impact

**US population 18-49 years:**
**August 2000 US population estimate = 130 million**
**Background incidence of hemorrhagic stroke = 8/100,000***
**Estimated 10,400 hemorrhagic strokes/year**

***Sacco, 1998, 2000; Petitti, 1997**

## Annual Public Health Impact18 - 49 years

## Public Health Impact

**Attributable risk in 18-49 age group:**
**200- 500 hemorrhagic strokes/year**
**Attributable risk in ******** 50 age group: ??**
**Attributable risk for the entire US population is therefore likely to be greater than for 18-49 age group**

## Criteria for Causal Association

**Temporal Relationship**
**Strength of the association**
**Dose response relationship**
**Biological plausibility**
**Consistency with other knowledge**
**Replication of the findings**

**Notes:**
Cartoon of risk by time

## Strength of Association

**PPA appetite suppressant (1st 3 days): **
**OR = 15.9 (95% LCL 2)**
**PPA cough/cold (1st day):**
**OR = 3.1 (95% LCL 1.2)**

**Notes:**
Explain that OR probably diluted by wide range of doses

## Dose Response 

**Yale study: Increased risk of hemorrhagic stroke with doses of PPA above 75 mg/day**
**FDA exploratory analysis: Increased risk of hemorrhagic stroke with PPA doses above 75 mg/day**
**Case review 2000: All 22 reports were with 75 mg preparations**

## Biological Plausibility

**PPA = sympathomimetic amine**
**Demonstrated pressor effects**
**Clear cut tachyphylaxis**
**Pressor effect greater for sustained release **

## Blood Pressure Response to PPA Challenge in a Large Population

**Blood Pressure Increase**

**% of Population**

**4mmHg**

## Consistency with Other Knowledge

**Numerous case reports in the literature**
**Kase, 1987; Lake, 1990**
**Lake - largest series, 24 cases ICH, 15 hypertensive encephalopathy/seizure, all with onset <24 hrs, most at 75 mg/day **
**O’Neill and Van de Carr Study**
**Case reviews 1984, 1991, 2000**

## Summary

**Hypothesis of increased risk of hemorrhagic stroke with early PPA use generated from case reports **
**Well designed prospective case control study strongly supports FDA hypothesis**
**Criteria for causality largely  fulfilled**
**Estimated 200-500 strokes/yr in young people potentially preventable**

## Conclusions

**The use of PPA as treatment for cough/cold symptoms & as an appetite suppressant confers an increased risk of hemorrhagic stroke in young people.**
**Substantial public health burden: in excess of 200-500 hemorrhagic strokes/year attributable to PPA**
**There is evidence to suggest that the risk of hemorrhagic stroke may be higher with PPA doses at or above 75 mg****/day.**

## Team: OPDRA/ Office of Biostatistics 

**Parivash Nourjah, PhD**
**David Graham, MD, MPH**
**Anne Trontell, MD, MPH**
**Julie Beitz, MD**
**Joslyn Swann, RPh**
**Yi Tsong, PhD**
**Stella Machado PhD**
**Robert O’Neill, PhD**

## Slide 46

## Back-up slides

## Pseudoephedrine (PSE) Hemorrhagic Stroke cases

**1969 - August 2000**
**9 possible, 6 with PSE alone**
**cases reported 1987 - 1998**
**F: 6   M: 3    Age: Mean 57 (45 - 67) **
**Median time to onset - 2 hours**
**Dose unknown**

## Time Dependent Relationship between PPA and Hemorrhagic Stroke

**Time-Specific Hazard**

**Time**

**True Hazard or Risk**

**)**

## Relationship between the Time Contour of PPA Risk and Relative Risk

**Time-Specific Hazard**

**Time**

**True Hazard or Risk**

**Observed RR**
**(Short Time Period)**

**Observed RR**
**(Longer Time Period****)**

## Public Health Impact

**Attributable risk = % of strokes attributable to PPA exposure & which could be prevented by removing exposure**
**Pc { (RRa - 1)/RRa}***
**	****	****Pc = % cases exposed**
**	****	****RRa = adjusted relative risk (adjusted OR)**

***Greenland, 1999**

## Public Health Impact contd

**Attributable risk estimates:**
**PPA first use (cough/cold) = 1% **
**104 cases/year **
**PPA appetite suppressant = 1%**
**90 cases/year**

## Public Health Impact -Attributable Risk Calculation

**{8/702} x 130 million = PPA first use cough cold AR = 120**
**{6/702} x 130 million = PPA appetite suppressant use AR = 90**
**Correction factor for excluded cases 702/1714 =0.41**

## Case DefinitionHemorrhagic Stroke

**Strict diagnostic criteria**
**clinical: signs/symptoms of hem. stroke**
**diagnostic: CT/ MRI/LP**
**Medical records of suspected cases reviewed by investigator, blinded to exposure status**
**Minimizes ****misclassification**** of cases**

## Exposure Definition/Ascertainment

**Exposure = PPA use**
**exposure defined, “first use”, “any use”**
**exposure window identified**
**exposure confirmed  by “PI book”**
**Interviewer bias minimized**
**blinded to exposure drug**
**randomly assigned to cases/controls**

## Strategies for Reducing Recall Bias

**Cases with stroke more likely to remember event surrounding stroke than controls (no stroke)**
**controls identified/interviewed within short time**
**focal time matched to case’s time of stroke**
**data collected on *****all *****medicines used**
**date prompts e.g birthdays**

## Total Number PPA dose units sold annually*

**1995       1996****	****   1997       1998       1999**
**  ****8.8         8.4           6.0          6.2          6.0**
**Numbers in billions**
***IMS HEALTH combined data from Provider Perspective****TM**** & Retail Perspective****TM**

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## Sensitivity Analysis for Addressing Bias due to Sparse Data

***Repeated 10 times, avg point estimate = 2.6**
****Repeated 10 times, avg point estimate = 6.9**

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