PHENYLPROPANOLAMINE & RISK OF HEMORRHAGIC STROKE:

Final Report of The Hemorrhagic Stroke Project

# May 10, 2000

Prepared by: Ralph I. Horwitz, M.D.

> Harold H. Hines Jr. Professor of Medicine and Epidemiology
>
> Yale University School of Medicine
>
> Lawrence M. Brass, M.D.
>
> Professor of Neurology and Epidemiology and Public Health
>
> Yale University School of Medicine
>
> Walter N. Kernan, M.D.
>
> Associate Professor of Medicine
>
> Yale University School of Medicine
>
> Catherine M. Viscoli, Ph.D.
>
> Associate Research Scientist

##### Yale University School of Medicine

> On Behalf of the HSP Investigators

EXECUTIVE SUMMARY

Case reports have linked exposure to phenylpropanolamine (PPA) to the
occurrence of hemorrhagic stroke. Many of the affected patients have
been young women using PPA as an appetite suppressant, often after a
first dose. To further examine the association between PPA and
hemorrhagic stroke, we designed a case-control study involving men and
women ages 18 to 49 years who were hospitalized with a subarachnoid
hemorrhage (SAH) or intracerebral hemorrhage (ICH). Eligible case
subjects had no prior history of stroke and were able to participate in
an interview within 30 days of their event. Case subjects were recruited
from hospitals in four geographic regions of the United States. For each
case subject, random digit dialing was used to identify two control
subjects who were matched on age, gender, race, and telephone exchange.
Cases and control subjects were interviewed to ascertain their medical
history, health behaviors, and medication usage. A subject was
classified as exposed to PPA if they reported use within 3 days of the
stroke event for case subjects or a corresponding date for control
subjects, and the exposure was verified.

The final study cohort comprised 702 case subjects and 1376 control
subjects. All control subjects were matched to their case subjects on
gender and telephone exchange. Age matching was successful for 1367
controls (99%) and ethnicity matching was achieved for 1321 controls
(96%). For the association between hemorrhagic stroke and any use of PPA
within three days, the adjusted odds ratio was 1.49 (lower limit of the
one-sided 95% confidence interval (LCL)=0.93, p=0.084). For the
association between hemorrhagic stroke and PPA use in cough-cold
remedies within the three-day exposure window, the adjusted odds ratio
was 1.23 (LCL=0.75, p=0.245). For the association between hemorrhagic
stroke and PPA use in appetite suppressants within the three-day
exposure window, the adjusted odds ratio was 15.92 (LCL=2.04, p=0.013).
For the association between PPA in appetite suppressants and risk for
hemorrhagic stroke among women, the adjusted odds ratio was 16.58
(LCL=2.22, p=0.011). For first dose PPA uses among women, the adjusted
odds ratio was 3.13 (LCL= 1.05, p = 0.042). All first dose PPA use
involved cough-cold remedies.

In conclusion, the results of the HSP suggest that PPA increases the
risk for hemorrhagic stroke. For both individuals considering use of PPA
and for policy makers, the HSP provides important data for a
contemporary assessment of risks associated with the use of PPA.

INTRODUCTION

Phenylpropanolamine (PPA) is a synthetic sympathomimetic amine
structurally similar to pressor amines (i.e., epinephrine,
phenylephrine, and ephedrine) and central nervous system stimulants
(i.e., ephedrine, amphetamine). It is a common ingredient in cough-cold
remedies and appetite suppressants. Each year, billions of doses are
consumed in the United States, making PPA one of the most commonly used
non-prescription medications(1).

Since 1979, over 30 published case reports have described the occurrence
of intracranial hemorrhage after PPA ingestion(1-3). Early reports
involved diet pills including both PPA and caffeine(4-7), a combination
that was removed from the market in 1983 because of abuse potential(8).
Later reports involved use of PPA alone(9, 10), often as a reported
first-ever dose (7, 11-14). Like the earlier ones, however, the later
reports primarily involved PPA in diet pills. Affected patients were
most commonly young persons, particularly women, ages 17 to 45 years. At
least five reports, however, involved PPA in cough cold
preparations(15-19).

Other than case reports, there has been only one epidemiologic study of
PPA and stroke, published in 1984(20). Investigators at a large health
maintenance organization examined the occurrence of cerebral hemorrhage
among patients ages less than 65 years who filled a prescription for PPA
during 1977-1981. The relative risk for hemorrhage for PPA users
compared to non-users was 0.59 (95% confidence interval 0.03-2.9). Since
the relative risk was less than one and the upper bound of the
confidence interval was about three, the authors concluded that any
hemorrhage risk related to PPA, if present at all, is very small.

Responding to on-going concern about PPA and risk for hemorrhagic
stroke, in 1992 the United States Food and Drug Administration joined
with manufacturers of products containing phenylpropanolamine to
recommend the conduct of an epidemiological study of the association.
Because several case reports involved young women using PPA as an
appetite suppressant, often after a first dose, the FDA and
manufacturers identified women as having high priority in research
planning. In response, the investigators of this research designed and
implemented the Hemorrhagic Stroke Project (HSP), with three co-equal
specific aims: Among men and women ages 18-49 years, to estimate the
association between PPA and hemorrhagic stroke; Among the same target
group, to estimate the association between PPA and hemorrhagic stroke by
type of PPA exposure (cough-cold remedy or appetite suppression); And
among women ages 18-49 years, to estimate: a) the association between
first use of PPA and hemorrhagic stroke and b) the association between
PPA in appetite suppressants and hemorrhagic stroke.

METHODS

**Recruitment and Classification of Patients with Hemorrhagic Stroke**

Between December 1994 and July 1999, we identified potential case
subjects from two hospital networks located in Connecticut/Southern
Massachusetts and Southern Ohio/Northern Kentucky and two tertiary care
hospitals in Providence, Rhode Island and Houston, Texas through active
surveillance of all admissions (See Appendix A for list of hospitals).
Surveillance involved review of admission rosters and direct monitoring
of admissions by one or more designated individuals, such as a discharge
planner or stroke nurse. As a check on the completeness of case
ascertainment, discharge rosters were reviewed from each participating
hospital.

Case subject eligibility criteria included admission to a participating
hospital, age between 18 and 49 years (inclusive) and symptomatic
primary subarachnoid hemorrhage (SAH) or primary intracerebral
hemorrhage (ICH). Subdural hematomas and hemorrhages related to ischemic
infarctions, trauma, thrombolytic therapy, or cerebral vein thrombosis
were not considered primary events and were not eligible for this study.
A SAH was diagnosed based on clinical symptoms and specific diagnostic
information. Required symptoms included sudden, severe headache, stiff
neck or change in level of consciousness. Required diagnostic
information included the presence of a high intensity signal in the
subarachnoid space on computed tomography, or xanthochromasia on lumbar
puncture not explained by other etiologies (e.g. liver disease,
increased CSF protein, hypervitaminosis A). An ICH was diagnosed by
symptoms (sudden headache, focal neurological symptoms, or change in
consciousness) accompanied by a computed tomographic (CT) scan showing a
hyperintense signal within brain parenchyma. Magnetic resonance imaging
was accepted for the diagnosis of SAH or ICH only if other studies were
not diagnostic. Subjects were ineligible for enrollment if they died
within 30 days, were not able to communicate within 30 days, had a
previously diagnosed brain lesion predisposing to hemorrhage risk (e.g.
arteriovenous malformation, vascular aneurysm, or tumor), or a prior
stroke. We also excluded patients who first experienced stroke symptoms
after being in the hospital for 72 hours (e.g., for an unrelated
matter).

Permission to contact each potential case subject was sought from the
treating physician. If permission were received, a researcher met with
the patient and reviewed pertinent data to confirm eligibility.

Once subject interviews were completed and medical records were
acquired, a second and final check on eligibility was completed at the
central office in New Haven by a researcher who was kept unaware of
medication exposures. This procedure was designed to ensure uniform
standards for documentation and eligibility across all research sites.
The researcher reviewed medical records and all study forms except the
interview booklet. (For subjects enrolled in the Ohio/Kentucky site,
medical records were reviewed on site. Study forms, however, were also
checked in New Haven). Missing radiology or laboratory data was
obtained. Patients with uncertain eligibility were reviewed with the
local investigator and the New Haven investigators before being
disqualified.

**Recruitment of Controls**

We attempted to identify two matched controls for each case subject.
Matching criteria included: 1) gender; 2) ethnic group (black versus
non-black); and 3) age (within 3 years for case subjects less than 30
years and within 5 years for cases 30 years or over). In addition, all
control subject interviews had to be completed within 30 days of the
case's stroke event to minimize seasonal differences in the likelihood
of exposure to cough-cold remedies. A computer-generated list of random
telephone numbers (matching the first three digits of the case subject
telephone number) was used to identify potential control subjects.
Eligibility criteria for control subjects were the same as for case
subjects except for those criteria related to the stroke event.

**Subject Interviews**

Eligible patients were invited to participate and give verbal informed
consent. During the consent procedure, all subjects (cases and controls)
were told that the study was designed to examine causes of hemorrhagic
stroke in young persons without specific mention of PPA or other
potential risk factors. Case subjects who did not speak English (n = 35)
were interviewed using a translator who, with five exceptions, was not a
relative or acquaintance. Most case-subject interviews were conducted in
the hospital, but some were completed at home and three were completed
by telephone. Most control-subject interviews were conducted in person
in the control subject's home, a doctor's office, or other convenient
location (44 were conducted by telephone). Control subjects were offered
twenty dollars to defray their expenses.

**Specification of Focal Time**

The first step of the interview process was to determine the focal time
for each case subject. This time refers to the calendar day (i.e. index
day) and time of day that marked the onset of symptoms plausibly related
to hemorrhage and that caused the case subject to seek medical
attention. The correct assignment of a focal time was critical because
exposures to PPA were defined in relation to this temporal anchor (i.e.,
only exposures that occurred prior to the focal time are relevant to the
analysis). To establish the focal time, we obtained from each case
subject a detailed account of his or her symptoms from onset to
diagnosis. Additional information was obtained from acquaintances or
witnesses to the case subject's illness.

Some patients with SAH or ICH may have a transient headache hours or
days before the event that actually causes them to seek medical
attention(21). These preceding symptoms have been termed "warning leaks"
or "sentinel headaches"(22). The cause of these sentinel headaches is
not known, although clinicians infer that some of them may be due to
minor bleeding(23). As expected, we encountered patients with sentinel
headache and recognized the possibility that the first onset of bleeding
may have coincided with that symptom. Since we defined the focal time by
the onset of the symptoms that actually brought them to medical
attention, we needed an additional research strategy to account for the
possibility of an earlier onset of bleeding. Accordingly, we defined an
alternate focal time as the time of onset of the sentinel headache. A
separate interview was conducted for this alternate focal time (for the
case and matched controls). How data on the alternate focal time were
analyzed is described below in the statistical analysis section.

The focal time for control subjects was established according to two
rules: first, it occurred on one of the 7 days prior to the control
interview; and second, it was matched to the case subject's focal time
according to day of week and time of day. For example, if the case
subject's focal time occurred on a Monday at 2:00pm and their control
subject was interviewed on a Thursday, then the focal time for the
control subject interview would be 2:00pm on the Monday preceding the
control interview. We maintained a short interval between control
subjects' focal times and interview dates to improve control subjects'
recall of pre-focal time exposures; the short interval was necessary to
balance case subjects' greater stimulation for recall of exposures
occurring before their stroke. The focal time matching was intended to
minimize differences between case subjects and control subjects for
differences in medication use and other exposures (e.g. alcohol,
cigarettes) that may occur by the day of week (e.g., weekday vs.
weekend) and time of day.

**Ascertainment of Exposure Data and Other Subject Information**

Case and control subjects were interviewed by a trained interviewer
using a structured questionnaire developed for this study. To assist
subjects in recalling details of their medication use, they were asked
to refer to a calendar for the period encompassing the index date
(before the focal time) and the preceding 14 days. The calendar was
marked with notable personal events, such as trips, birthdays and
doctor's visits that occurred during this period. As a memory aid,
subjects were asked to recall if specific symptoms of a cold or flu
(i.e., cough, runny nose, nasal congestion, or sore throat) were present
in this two-week period. If present, the subject was asked if they had
used any medication to treat the symptoms. The subject was then asked to
recall the names of any other medications (purchased over the counter or
prescribed by a doctor) taken during this time period. After all
volunteered medications were recorded, subjects were asked if they had
taken any of several specific classes of medications in the two-week
period before the focal time (i.e., aspirin, acetaminophen,
non-steroidal anti-inflammatory medications, anticoagulants, asthma
medications, and medications for depression). Subjects were specifically
asked about their lifetime use and last use of diet pills. For each
medication reported taken during the two-week period, details were
obtained regarding certainty of use (definite, probable, or uncertain)
and amount taken on the index day prior to focal time and on each of the
preceding three calendar days. For each medication, the timing and
amount of the last dose taken before the focal time was noted. Only uses
that were reported as probable or definite were counted in the analysis.

Verification of each reported medication was done after the interview.
Participants were asked to pick out reported brand-name medications from
a book containing photographs (Product Identification Book). They were
then asked to produce the actual container of each medication reported.
The exact name of the medication and the manufacturer's lot numbers were
recorded. If a container was not available, use of a brand name
medication was considered verified if the subject had identified it in
the Product Identification Book. Among 28 reported PPA uses in a three
day window for case subjects, 27 (96%) were verified. Among 35 reported
PPA uses for control subjects, 33 (94%) were verified.

To determine the active ingredients in each verified medication, we
relied on published sources(24, 25). For national brands and
prescription drugs that had possible formulation changes during the
study period and for generic or store brand medications, we verified
active ingredients directly with the manufacturer.

**Definition of Exposure**

The exposure window refers to the interval before the focal time when
subject's exposure status to PPA is assessed. For all analyses except
first-dose use, the exposure window was defined as the index day before
focal time and the preceding three calendar days. For first-dose use, a
subject was considered exposed if the PPA use occurred on the index day
before the focal time or on the preceding calendar day, with no other
PPA uses during the preceding two weeks. Subjects were only considered
exposed to PPA within the appropriate window if their reported exposure
was verified by the procedures described above. To maintain a consistent
reference group for all analyses, non-exposure was defined by no use of
PPA within two weeks of the index date.

**Sample Size**

The sample size was based on the need to determine if PPA, taken as a
first use, increases the risk of hemorrhagic stroke within 24 hours
among women ages 18-49. Based on available market data, we estimated
that 0.502% of controls would report an exposure to PPA within 24 hours
of the index date. For a one-tailed test of significance at the 0.05
level and 80% power to detect an odds ratio of 5.0 for first use
exposure in women, 324 female case subjects and 648 control subjects
were required. Because our research interest extended to men and to
exposures other than PPA, we doubled our sample size to include 350 men
and 350 women for a total of 700 case subjects and 1400 controls.

**Statistical Analysis**

In the first phase of the analysis, we compared case and control
subjects on a variety of clinical and demographic features, including
those used in matching. Statistical comparisons were made using
chi-square tests and the Fisher's exact test, where appropriate, for
categorical variables and the Student *t*-test for continuous variables
(SAS Institute Inc, Cary, North Carolina). In the second phase of the
analysis, conditional logistic models for matched sets (with a variable
number of controls per case) were used to estimate odds ratios, lower
limits of the one-sided 95% confidence intervals and p-values for the
risk factors under investigation. We report one-tailed statistical
results because the focus of this research was restricted to the effect
of PPA in increasing the risk of stroke. Each logistic model was
estimated with two mutually exclusive, binary exposure terms: the first
term captured the subject's primary exposure status as defined by the
specific aim (e.g., PPA use in 3-day window; yes/no); the second term
captured users of PPA who were not exposed according to the primary
definition (e.g., no PPA use in the three day window, but some PPA
exposure within two weeks of the focal time). This modeling technique
was employed in order to retain all matched subject-sets in the
estimation of the primary exposure of interest while maintaining a
consistent reference group of no-PPA use in two weeks for all analyses.
Unadjusted estimates were calculated using exact methods (LogXact
Program, version 2.1, Cytel Software Corporation, Cambridge, MA).

In multivariate conditional logistic models (using asymptotic methods),
we adjusted for race (black compared with non-black) because not all
cases and controls were successfully matched on this factor, and for
history of hypertension (yes/no) and current cigarette smoking (current
compared with never or ex-) because these are the major risk factors for
SAH or ICH(26, 27). We also examined other subject features to determine
if any of them, when added to this basic adjusted model, altered the
matched odds ratio by at least 10%. Clinical features examined included
body mass index, diabetes, polycystic kidney disease, congestive heart
failure, sickle cell anemia, and clotting disorders. Other subject
features included education (less than high school/high school or more),
family history of hemorrhagic stroke in a first degree relative,
consumption of more than two alcoholic beverages per day, cocaine use
within one day of the index day, current oral contraceptive use, and
several other pharmacological exposures. The final model included race,
current cigarette use, hypertension, and any features that changed the
adjusted matched odds ratio by at least 10%.

The study design incorporated two interim examinations of the data. As
specified in the protocol, each interim analysis examined the
association between stroke and any PPA use in the three-day window for
the entire cohort and first PPA use in women. To preserve the specified
alpha level for statistical inference (type I error rate), the
O'Brien-Fleming multiple testing procedures were used for testing the
significance of effect estimates(28). For three looks at the data (two
interim and one final look) and a final alpha level of 0.05 for a
one-tailed test of each objective, the O'Brien-Fleming chi-square
statistics corresponded to one-tailed p-values of 0.008 (first look),
0.023 (second look), and 0.044 (final look).

As described above, we encountered patients with sentinel symptoms for
whom we defined an alternate focal time. If the actual disease onset is
defined by the alternate focal time rather than the primary focal time,
an analysis based on the latter could lead to a biased estimate of the
odds ratio by two mechanisms. First, case subject exposure to PPA
between the alternate (earlier) and primary (later) focal time may
actually be in response to the disease (and not a potential cause of the
disease). If such exposures occur within the appropriate time window,
however, they would be counted in the analysis using the primary focal
time and would lead to an overestimate of the odds ratio. This bias is
sometimes referred to as temporal precedence bias(29, 30). Second, case
subject exposure to PPA before the alternate focal time may actually be
causally associated with the disease. If these earlier exposures were
outside the appropriate time window for the primary focal time analysis,
however, they would not be counted and the error would lead to an
underestimate of the odds ratio. To examine the potential effect of
these two sources of bias, we performed two ancillary analyses, one
excluding all subject sets where the case subject had a possible
sentinel symptom and one using the alternate focal time.

**Oversight**

An external Scientific Advisory Group (SAG) operated autonomously from
the investigators and study sponsors and provided general oversight for
the conduct of the HSP. The SAG reviewed the research protocol and
suggested revisions, reviewed research progress, developed criteria for
early termination, and evaluated interim and final analyses.
Nevertheless, the investigators accept all responsibility for the
conduct of the study, the analysis of the data, and the interpretation
of the results. A list of advisory group membership is included at the
end of this report.

RESULTS

**Study Participants**

Between December 1994 and July 1999, 1,714 potentially eligible patients
with hemorrhagic stroke were identified (Table 1). Among these, 784
subjects were ineligible for enrollment (389 died, 194 were unable to
communicate within 30 days of the event, 120 had a history of stroke, 48
had a known brain tumor or arteriovenous malformation, and 33 were in
the hospital over 72 hours before their event). Among the 930 eligible
subjects, 222 were not enrolled (182 were not contacted within 30 days,
37 declined to give informed consent, and for 3 their physician did not
give permission for contact). The total number of eligible case subjects
enrolled was 708. There were no significant differences (p\<0.05) in age
or ethnicity between the 708 enrolled patients and the 222 eligible
patients who were not enrolled. Subjects in the enrolled case group,
however, were more likely to be female (55% compared with 45%, p = 0.02)
and to have a SAH (60% compared with 47%, p \< 0.01). Six patients were
not included in the final analysis because no eligible controls were
identified (three patients), the interview date was over 30 days from
the stroke event (two patients), or the focal time could not be
determined (one patient). Thus, the final case group comprised 702
subjects, including 425 subjects (60%) with a SAH and 277 (40%) with an
ICH. Hemorrhage was associated with an aneurysm in 307 patients (44%),
an arteriovenous malformation in 50 patients (7%), and a tumor in one
patient (0.1%). (See Appendix B for additional details on case
enrollment)

Two control subjects were located for 674 case subjects (96%) and one
control subject for 28 case subjects (4%). All control subjects were
matched to their case subjects on gender and telephone exchange. Age
matching was successful for 1367 controls (99%) and ethnicity matching
was achieved for 1321 controls (96%). On average, for each case subject,
we called 151 telephone numbers (range 3-1119) and identified 2.8
eligible persons for each enrolled control (range 1-12).

The mean interval between the case index date and the interview date was
13 days (range 0 to 30) for case subjects and 19 days for their matched
control subjects (range 0 to 35). All control subjects except six were
interviewed within 30 days of the case subject's index date. We allowed
enrollment of six controls within an interval of 31-35 days since the
purpose of interviewing controls within 30 days of the case subject's
index date was simply to ensure seasonal similarity when collecting data
on pharmaceutical exposures.

Table 2 shows selected characteristics of case and control subjects.
Compared to control subjects, case subjects were significantly (p\<0.05)
more likely to be black (21% compared with 17%). Case subjects were also
more likely to report lower educational achievement (20% did not
graduate from high school compared with 9% of control subjects), current
cigarette smoking (51% compared with 30%), a history of hypertension
(39% compared with 20%), family history of hemorrhagic stroke (9%
compared with 5%), heavy alcohol use (14% compared with 7%), and recent
cocaine use (2% compared with \<1%). For all other clinical variables
examined, case and control subjects were not dissimilar.

Table 3 shows non-PPA pharmacological exposures of case and control
subjects. Case subjects were significantly (p\<0.05) less likely to
report use of NSAIDS and significantly more likely to report use of
caffeine and nicotine in the three days before their focal time.

To identify variables for inclusion in subsequent multivariable models,
we sequentially tested each clinical feature (Table 2) and
pharmacological exposure (Table 3) in the basic conditional logistic
model that included race, hypertension, and current cigarette smoking.
Under any PPA exposure definition, only education changed the adjusted
odds ratio for the association between PPA and hemorrhagic stroke by
more than 10% and was included in all subsequent models.

**Association Between PPA and Hemorrhagic Stroke**

Our first co-equal specified aim was to determine whether PPA users,
compared to non-users have an increased risk of hemorrhagic stroke. In
Table 4, frequencies are shown for exposures to PPA in an unmatched
format for the case and control subjects, with unadjusted and adjusted
matched odds ratios provided. (See Appendix C for exposures presented in
matched format.) The odds ratios were calculated from conditional
logistic models for matched sets; the adjusted models included the same
four variables: race, history of hypertension, current cigarette
smoking, and education. For any use of PPA within three days (either for
cough-cold remedy or appetite suppression), the unadjusted odds ratio
was 1.67 (p=0.040) and the adjusted odds ratio was 1.49 (lower limit of
the one-sided 95% confidence interval (LCL)=0.93, p=0.084).

Our second co-equal specific aim was to estimate the association between
use of PPA and hemorrhagic stroke according to type of PPA exposure. The
results are shown in Table 4. (See Appendix C for exposures presented in
matched format.) For the association between PPA use in cough-cold
remedies within the three-day exposure window, the unadjusted odds ratio
was 1.38 (p=0.163). The adjusted odds ratio was 1.23 (LCL=0.75,
p=0.245). For the association between PPA use in appetite suppressants
within the three-day exposure window, the unadjusted odds ratio was
11.98 (p=0.007) and the adjusted odds ratio was 15.92 (LCL=2.04,
p=0.013).

To examine the relation between recency of PPA exposure and risk for
hemorrhagic stroke, we calculated odds ratios according to the timing of
most recent PPA use (Table 5). For this analysis, the pre-specified
definition for current use was use of any PPA-containing product on the
index day before focal time or the preceding calendar day. Prior use was
defined as use two or three calendar days before the focal time. As
shown in the table, the odds ratio was slightly higher for current use
(adjusted OR (AOR)=1.61, LCL=0.93, p=0.078) than for prior use
(AOR=1.16, LCL=0.47, p=0.393). Within current use, we then calculated
odds ratios according to first use or not-first use. First use was
defined as current use with no other use within the prior two weeks.
Not-first use included other uses within the two-week interval. The odds
ratio was higher for first use (AOR=3.14, LCL=1.16, p=0.029) than for
not-first use (AOR=1.20, LCL=0.61, p=0.329). All first uses of PPA
(n=13) reported in these data were in cough-cold remedies.

Our final co-equal specific aim was to estimate the association between
PPA and risk for hemorrhagic stroke among women for two exposure
definitions: appetite suppressant use within three days and first dose
use (See Appendix D). For the association between PPA in appetite
suppressants and risk for hemorrhagic stroke among women, the unadjusted
odds ratio was 12.19 (p=0.006) and the adjusted odds ratio was 16.58
(LCL=2.22, p=0.011). Among HSP subjects, all appetite suppressant use
within the three-day exposure window occurred among women. For first
dose PPA uses, eleven of the 13 exposures were among women (seven cases
compared with four controls). The unadjusted odds ratio was 3.50
(p=0.039) and the adjusted odds ratio was 3.13 (LCL= 1.05, p = 0.042).
Appendix C shows exposure data for cases and controls in a matched
format.

**Additional Analyses**

Based on the findings that risk for hemorrhagic stroke seemed to be
concentrated among current users, we examined the association between
current PPA dose and risk for hemorrhagic stroke. Among 21 exposed
control subjects, the median current dose of PPA (i.e., total amount
taken on the index day or preceding day) was 75mg. Analysis according to
dose shows that the odds ratio was higher for current doses above the
median (\>75mg) (AOR=2.31, LCL=1.10, p=0.031) than for lower doses
(AOR=1.01, LCL=0.43, p=0.490). Among first dose users, four of eight
cases and two of five controls were exposed to \>75mg of PPA.

To examine the potential effect of ambiguity in the correct focal time,
we recalculated the odds ratios after excluding all 154 case subjects
who were classified as having a definite (n=76) or uncertain (n=78)
sentinel symptom. The magnitude of the adjusted odds ratios did not
change substantially (see Appendix E). We also recalculated the odds
ratios using the alternate focal time data for the 53 patients who, with
their matched control subjects, had a completed interview for this focal
time. Again, the adjusted odds ratios did not change substantially (see
Appendix F).

**Description of Case and Control Subjects**

Table 6 describes the 27 case subjects who reported an exposure to PPA
on their index day before focal time or during the preceding three days.
Among the 27 exposed case subjects, 21 (78%) were women and 6 (22%) were
men. Known risk factors for SAH or ICH (i.e., smoking, hypertension)
were present for 18 subjects (66%). About half of all exposures to PPA
occurred within 6 hours of the focal time, with a range of 6 minutes to
3.5 days and about half of all exposures (n = 17) involved slow release
preparations. The amount of PPA consumed at the last dose ranged from 7
mg to 150 mg (mean 82 mg). Eight of 27 last dose exposures (30%)
exceeded normal adult doses of 50 mg for immediate release preparations
and 75 mg for sustained release preparations(31).

Table 7 describes the 33 control subjects who reported an exposure to
PPA on their index day before focal time or during the preceding three
days. Among the 33 exposed case subjects, 20 (61%) were women and 13
(39%) were men. Known risk factors for SAH or ICH (i.e., smoking,
hypertension) were present for 18 control subjects (54%). One third of
all exposures to PPA occurred within 6 hours of the focal time, with a
range of 40 minutes to 3.2 days and about half of all exposures (n = 17)
involved slow release preparations. The amount of PPA consumed at the
last dose ranged from 12 mg to 150 mg (mean 61 mg). Five of 32 last
known dose exposures (16%) exceeded normal adult doses. In summary,
compared to PPA-exposed case subjects, exposed control subjects were
less likely to be female (61% compared with 78%), to have stroke risk
factors (54% compared with 66%), to consume PPA within 6 hours of the
focal time (33% compared with 52%), and to take excessive doses of PPA
(16% compared with 30%). Further details of PPA-exposed and non-exposed
subjects are presented in Appendix G.

DISCUSSION

In the Hemorrhagic Stroke Project of subjects between ages 18 and 49
years, PPA use was associated with an increased risk for hemorrhagic
stroke. The increased risk was evident for PPA used as an appetite
suppressant and for first use exposure. Because first uses of PPA in the
HSP always involved cough-cold remedies, the association of PPA with
risk for hemorrhagic stroke is present for both customary indications
for PPA (as a cough-cold remedy and an appetite suppressant). The
association of PPA with risk for hemorrhagic stroke was evident in the
overall group of case and control subjects and among women. Because so
few men were exposed to PPA in the HSP (n=19), we were unable to
determine if their risk for hemorrhagic stroke (with use of PPA) is
different from that of women.

Prior to the HSP, information concerning the association between PPA and
risk for hemorrhagic stroke in humans came from clinical trials(8), case
reports(2), and one epidemiological study(20). Clinical trials on the
effectiveness of PPA are not informative on the risk of brain hemorrhage
because they did not enroll enough patients to observe occurrences of
this rare event. The one epidemiologic study found no association
between PPA and hemorrhagic stroke, but design limitations reduce its
contribution to the assessment of PPA safety. The only direct evidence
for an association between PPA and risk for hemorrhagic stroke in humans
has come from case reports. Although these reports effectively called
attention to the possible association between PPA and hemorrhagic
stroke, the absence of control subjects means that these studies cannot
provide evidence that meets the usual criteria for valid scientific
inference. The HSP, therefore, provides the most comprehensive and valid
evidence to date on the association between PPA and risk for hemorrhagic
stroke.

Other than a valid association between PPA and stroke, possible
alternative explanations for our findings include residual confounding,
bias in the design of the study, and chance findings in the analysis.
Residual confounding refers to incomplete adjustment for factors related
to both exposure and outcome. Although some residual confounding may be
present within the HSP, our data provide little support for the
presumption that it is significantly distorting the observed association
between PPA and hemorrhagic stroke. In particular, adjustment for known
potential confounders did not produce odds ratios that were markedly
different from the unadjusted figures (Tables 4 and 5).

Biases that most commonly affect the design of case-control studies
include temporal precedence bias, recall bias, and selection bias.
Temporal precedence bias refers to a systematic error in which an
exposure is counted although it occurs after the onset of the disease
under study, often in response to disease symptoms(30). We checked for
temporal precedence bias with specific analytic strategies for patients
with sentinel symptoms and found no evidence that it has an important
influence on the measured odds ratios.

Recall bias refers to the tendency of case subjects, compared with
control subjects, to have more or less complete recall of exposures or
to report exposures that may never have happened(32). Although it is
possible that our case subjects over-reported PPA exposure in an attempt
to explain their illness, in our data case subjects were no more likely
than control subjects to report exposures to aspirin or non-PPA oral
sympathomimetics. These negative findings suggest that recall bias was
not an important source of distortion in the HSP, especially considering
the well-publicized risk of hemorrhage with aspirin. It seems likely,
furthermore, that case-subjects in the HSP may have had impaired recall
of exposures due to brain injury. This impairment would have biased the
study toward a finding of no association between PPA and hemorrhagic
stroke. Our data provide some evidence for a bias in this direction
because case-subjects in the HSP more frequently reported "uncertain"
exposures to PPA than control subjects. When these "uncertain" exposures
are counted, the odds ratios increase by over 10% for all exposure
definitions except for first dose use. For first dose use the odds ratio
falls from 3.14 (p = 0.029) to 2.88 (p = 0.044). In addition, to address
differential recall stimulus we set the index day for control subjects
within one week of their interview (compared with up to 30 days for case
subjects). The close proximity of the index date and interview date for
control subjects was intended to overcome the imbalance in stimulus for
recall between controls (who experienced no major life event on the
index date) and cases (who did). Although recall bias is commonly
discussed in relation to case-control research, it rarely has a
meaningful impact on research findings(33, 34).

Selection bias refers to the preferential referral to a case-control
study of case or control subjects with (or without) the exposure under
study(35). Selection bias in the HSP might result from publicity about
PPA and stroke, leading physicians to preferentially seek a diagnosis of
hemorrhage in a PPA user or to preferentially refer a patient to the
study if there were a history of PPA use(36). We adopted several
strategies to reduce the possibility of selection bias, including active
case surveillance and enrollment of subjects who met our eligibility
criteria, regardless of the diagnostic impression of their physicians.
To check for possible selection bias, we compared eligible, enrolled
case-subjects with eligible, non-enrolled patients and found no
differences in age or ethnicity. Non-enrolled patients, however, were
more likely to be female and to have an ICH rather than a SAH. We did
not assess the eligible, non-enrolled patients for their ability to
communicate within 30 days; if we had, it is likely that many would have
been reclassified as non-eligible. Because ICH is more likely than SAH
to impair communication, this reclassification would be expected to
narrow the difference between eligible, enrolled and eligible,
non-enrolled patients in stroke type. Another potential source of
selection bias in the HSP is non-participation by eligible control
subjects who did not answer their telephone or who refused
participation. We do not know if such persons were more or less likely
to use PPA than the controls who agreed to participate.

Chance seems an unlikely explanation for our findings. Odds ratios for
appetite suppressant use and first use (all involving cough-cold
products) reached the conventional threshold for statistical
significance (p\<0.05). Although the odds ratio for the association
between any PPA use in three days did not reach this threshold, chance
remains an unlikely explanation for the observed value of 1.49
(p=0.084).

Several features of the HSP support a valid association between PPA use
and risk for hemorrhagic stroke. First, in addition to the finding of
elevated odds ratios that reached statistical significance, the
magnitude of the odds ratios for PPA use as an appetite suppressant
(15.92) and as a first use (3.14) were large in magnitude even after
adjustment for important clinical features. Second, these data show an
association with brain hemorrhage across the two major formulations of
PPA (i.e., cough-cold remedy and appetite suppression).

There are potential limitations to our research. First, because we
excluded dead and non-communicative patients we cannot know if PPA is
more or less associated with brain hemorrhage in these patients compared
with those studied. Epidemiologists have long recognized a form of
research bias termed prevalence-incidence bias that may occur if
survivors of a potentially fatal illness have a different clinical
profile from those who die(37). This bias may either increase or reduce
the odds ratio associated with an exposure under investigation. In the
HSP, for example, if PPA confers a survival advantage in hemorrhagic
stroke, the odds ratio among survivors will be spuriously increased. If
PPA increases mortality, on the other hand, the odds ratio among
survivors will be spuriously reduced. Although we cannot be fully
certain that prevalence-incidence bias has not affected the HSP, we are
unaware of a plausible mechanism by which PPA might increase or decrease
the likelihood of survival after a stroke.

A second possible limitation of our study is the number of case and
control subjects who were exposed to PPA (n=60). This number of exposed
subjects limits the opportunity for subgroup analysis. It is worth
noting, however, that the exposure rate observed in women for the first
dose use analysis (0.533%) achieved the rate anticipated in the research
design (0.502%). As a final limitation, the HSP interviewers were not
blinded to the case-control status of subjects and some were aware of
the study purpose. Blinding would have provided extra protection against
unequal ascertainment of PPA exposure in case subjects compared with
control subjects. Instead of blinding, we relied on a highly structured
and scripted interview instrument. Overall, none of the limitations are
sufficiently important to invalidate our findings.

In conclusion, the results of the HSP suggest that PPA increases the
risk for hemorrhagic stroke. For both individuals considering use of PPA
and for policy makers, the HSP provides important data for a
contemporary assessment of risks associated with the use of PPA.

HSP INVESTIGATORS

Ralph I. Horwitz, M.D.

Harold H. Hines Jr. Professor of Medicine and Epidemiology

Yale University School of Medicine

New Haven, Connecticut

Lawrence M. Brass, M.D.

Professor of Neurology and Epidemiology and Public Health

Yale University School of Medicine

New Haven, Connecticut

Joseph P. Broderick, M.D.

Professor of Neurology

University of Cincinnati College of Medicine

Cincinnati, Ohio

Thomas Brott, M.D.

Professor of Neurology

Mayo Medical School

Rochester, Minnesota

Edward Feldmann, M.D.

Professor of Neurosciences

Brown University School of Medicine

Providence, Rhode Island

Walter N. Kernan, M.D.

Associate Professor of Medicine

#### Yale University School of Medicine

New Haven, Connecticut

Lewis Morgenstern, M.D.

Assistant Professor of Neurology and Epidemiology

The University of Texas Medical School and School of Public Health

Houston, Texas

Catherine M. Viscoli, Ph.D.

Associate Research Scientist

Yale University School of Medicine

New Haven, Connecticut

Janet Lee Wilterdink, M.D.

Associate Professor of Neurosciences

Brown University School of Medicine

**SCIENTIFIC ADVISORY GROUP MEMBERS**

Louis C. Lasagna, M.D. (Chair)

Dean, Sackler School of Graduate Biomedical Sciences

Professor of Pharmacology and Experimental Therapeutics

Tufts University

J. P. Mohr, M.D.

Sciarra Professor of Neurology

College of Physicians and Surgeons

Columbia University

Samy Suissa, Ph.D.

Professor of Medicine and Epidemiology and Biostatistics

McGill University

REFERENCES

1\. **Morgan JP.** *Phenylpropanolamine. A critical analysis of reported
adverse reactions and overdosage* Fort Lee, New Jersey: Jack K. Burgess,
Inc.; 1986.

2\. **Lake CR, Gallant S, Masson E, Miller P.** Adverse drug effects
attributed to phenylpropanolamine: A review of 142 case reports.
*American Journal of Medicine*. 1990;89:195-208.

3\. **King J.** Hypertension and cerebral haemorrhage after Trimolets
ingestion. *Medical Journal of Australia*. 1979;2:258.

4\. **Kikta DG, Devereaux MW, Chandar K.** Intracranial hemorrhages due
to phenylpropanolamine. *Stroke*. 1985;16:510-512.

5\. **Fallis RJ, Fisher M.** Cerebral vasculitis and hemorrhage
associated with phenylpropanolamine. *Neurology*. 1985;35:405-407.

6\. **Johnson DA, Etter HS, Reeves DM.** Stroke and Phenylpropanolamine
use. *Lancet*. 1983:970.

7\. **McDowell JR, LeBlanc HJ.** Phenylpropanolamine and cerebral
hemorrhage. *The Western Journal of Medicine*. 1985;142:688-691.

8\. **Lasagna L.** *Phenylpropanolamine: A review* New York, NY: Wiley &
Sons, Inc.; 1988.

9\. **Maher LM.** Postpartum intracranial hemorrhage and
phenylpropanolamine use. *Neurology*. 1987;37:1686.

10\. **Forman HP, Levin S, Stewart B, Patel M, Feinstein S.** Cerebral
vasculitis and hemorrhage in an adolescent taking diet pills containing
phenylpropanolamine: case report and review of literature. *Pediatrics*.
1989;83:737-741.

11\. **Stoessl AJ, Young GB, Feasby TE.** Intracerebral haemorrhage and
angiographic beading following ingestion of catecholaminergics.
*Stroke*. 1985;16:734-736.

12\. **Kase CS, Foster TE, Reed JE, Spatz EL, Girgis GN.** Intracerebral
hemorrhage and phenylpropanolamine use. *Neurology*. 1987;37:399-404.

13\. **Traynelis VC, Brick JF.** Phenylpropanolamine and vasospasm.
*Neurology*. 1986;36:593.

14\. **Chung Y-T, Hung D-Z, Hsu, C-P, Yang, D-Y, Wu, T-C.**
Intracerebral hemorrhage in a young woman with arteriovenous
malformation after taking diet control pills containing
phenylpropanolamine: A case report. *Chinese Medical Journal*.
1998;61:432-435.

15\. **Humberstone PM.** Hypertension and cold remedies. *British
Medical Journal*. 1969;i:846.

16\. **Sloan MA, Kittner MA, Rigamonti D, Price TR.** Occurrence of
stroke associated with use/abuse of drugs. *Neurology*.
1991;41:1358-1364.

17\. **Bernstein E, Diskant BM.** Phenylpropanolamine: a potentially
hazardous drug. *Annals of Emergency Medicine*. 1982;11:311-315.

18\. **Tonks CM, LLoyd AT.** Hazards wtih monoamine-oxidase inhibitors.
*British Medical Journal*. 1965;i:589.

19\. **Rumbaugh CL, Fang HCH, Higgins RE, Bergeron RT, Segall HD, Teal
JS.** Cerebral microvascular injury in experimental drug abuse.
*Investigative Radiology*. 1976;11:282-294.

20\. **Jick H, Aselton P, Hunter JR.** Phenylpropanolamine and cerebral
haemorrhage. *Lancet*. 1984:1017.

21\. **Linn FHH, Wijdicks EFM, van der Graaf Y, Weerdesteyn-van Vliet
FAC, Bartelds AIM, van Gijn J.** Prospective study of sentinel headache
in aneurysmal subarachnoid hemorrhage. *Lancet*. 1994;344:590-593.

22\. **Mayer PL, Awad IA, Todor R, et al.** Misdiagnosis of symptomatic
cerebral aneurysm. Prevalence and correlation with outcome at four
institutions. *Stroke*. 1996;27(9):1558-63.

23\. **Edlow JA, Caplan LR.** Avoiding pitfalls in the diagnosis of
subarachnoid hemorrhage. *The New England Journal of Medicine*.
2000;342:29-36.

24\. **Medical Economics Company.** *Physicians\' Desk Reference*. 53 ed
Montvale: Medical Economics Company, Inc.; 1999.

25\. **Knodel LC, Young LL, Kendall SCe.** *Nonprescription Products:
Formulations and Features (\'98-\'99)* American Pharmaceutical
Association; 1997.

26\. **Longstreth WT, Koepsell TD, Yerby MS, van Belle G.** Risk factors
for subarachnoid hemorrhage. *Stroke*. 1985;16:377-385.

27\. **Teunissen LL, Rinkel GJ, Algra A, van Gijn J.** Risk factors for
subarachnoid hemorrhage: a systematic review. *Stroke*.
1996;27(3):544-9.

28\. **O\'Brien PC, Fleming TR.** A multiple testing procedure for
clinical trials. *Biometrics*. 1979;35:549-556.

29\. **Forsyth BW, Horwitz RI, Acampora D, et al.** New epidemiologic
evidence confirming that bias does not explain the aspirin/Reye\'s
Syndrome association. *Journal of the American Medical Association*.
1989;261:2517-2524.

30\. **Horwitz RI, Feinstein AR, Harvey MR.** Temporal Precedence and
other problems of the exposure-disease relationship. *Archives of
Internal Medicine*. 1984;144:1257-1259.

31\. **Trudeau TW, Wright W, Staff DRE.** Phenylpropanolamine. In:
Gelman CR, Rumack BH, Sayre NK, eds. *Drugdex System*. Englewood,
Colorado (Edition expires 12/1999): Micromedex Inc.

32\. **Schlesselman JJ.** *Case-Control Studies. Design, Conduct,
Analysis* New York: Oxford University Press; 1982.

33\. **Austin H, Hill HA, Flanders D, Greenberg RS.** Limitations in the
applications of case-control methodology. *Epidemiologic Reviews*.
1994;16:65-76.

34\. **Aitken J, Bain C, Ward M, Siskind V, MacLennan R.** How accurate
is self-reported family history of colorectal cancer? *American Journal
of Epidemiology*. 1995;141:863-871.

35\. **Breslow NE, Day NE.** *Statistical Methods in Cancer Research.
Volume I -The Analysis of Case-Control Studies* Lyon: International
Agency for Research on Cancer; 1980.

36\. **Jick H, Vessey MP.** Case-control studies in the evaluation of
drug-induced illness. *American Journal of Epidemiology*. 1978;107:1-7.

37\. **Sackett DL.** Bias in analytic research. *Journal of Chronic
Diseases*. 1979;32:51-63.

Table 1.

Assembly of Cohort

+----------------------------------------------------------+-----------+
|                                                          | > No.     |
+----------------------------------------------------------+-----------+
| > Hemorrhagic Strokes Identified (Dec. 1994 -- Aug.      | > 1,714   |
| > 1999)                                                  |           |
+----------------------------------------------------------+-----------+
|                                                          |           |
+----------------------------------------------------------+-----------+
| > Ineligible Subjects                                    | > 784     |
+----------------------------------------------------------+-----------+
| > Died within 30 days of stroke                          | > 389     |
+----------------------------------------------------------+-----------+
| > Not able to communicate within 30 days of stroke       | > 194     |
+----------------------------------------------------------+-----------+
| > Prior history of stroke                                | > 120     |
+----------------------------------------------------------+-----------+
| > Prior history of brain tumor or AVM                    | > 48      |
+----------------------------------------------------------+-----------+
| > In hospital \> 72 hours before stroke                  | > 33      |
+----------------------------------------------------------+-----------+
|                                                          |           |
+----------------------------------------------------------+-----------+
| > Eligible Subjects^1^                                   | > 930     |
+----------------------------------------------------------+-----------+
| > Not enrolled                                           | > 222     |
+----------------------------------------------------------+-----------+
| > Not contacted within 30 days                           | > 182     |
+----------------------------------------------------------+-----------+
| > Refused participation                                  | > 37      |
+----------------------------------------------------------+-----------+
| > No MD approval to contact                              | > 3       |
+----------------------------------------------------------+-----------+
| > Enrolled                                               | > 708     |
+----------------------------------------------------------+-----------+

# ^1^For non-enrolled subjects, stroke events were confirmed to be eligible but ability to communicate within 30 days of event was not assessed. 

# 

# Table 2.

# Sociodemographic and Clinical Features

# of Case and Control Subjects

+---------------------------------+---------+-----+---------+------+---+
|                                 | [       |     | [       |      |   |
|                                 | Cases^1 |     | Control |      |   |
|                                 | ^]{.und |     | s]{.und |      |   |
|                                 | erline} |     | erline} |      |   |
|                                 |         |     |         |      |   |
|                                 | (n=702) |     | (       |      |   |
|                                 |         |     | n=1376) |      |   |
+---------------------------------+---------+-----+---------+------+---+
|                                 | [No     | [%] | [No     | [%]  |   |
|                                 | .]{.und | {.u | .]{.und | {.un |   |
|                                 | erline} | nde | erline} | derl |   |
|                                 |         | rli |         | ine} |   |
|                                 |         | ne} |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| [Sociodemographic               |         |     |         |      |   |
| Features]{.underline}           |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| Female                          | > 383   | >   | > 750   | >    |   |
|                                 |         | 55% |         |  55% |   |
+---------------------------------+---------+-----+---------+------+---+
| Black race                      | > 146   | >   | > 232   | >    | \ |
|                                 |         | 21% |         |  17% | * |
+---------------------------------+---------+-----+---------+------+---+
|                                 |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| Age: \< 40                      | > 296   | >   | > 592   | >    |   |
|                                 |         | 42% |         |  43% |   |
+---------------------------------+---------+-----+---------+------+---+
| > 40-49                         | > 406   | >   | > 784   | >    |   |
|                                 |         | 58% |         |  57% |   |
+---------------------------------+---------+-----+---------+------+---+
|                                 |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| Education^2^: \<HS graduate     | > 143   | >   | > 121   | > 9% | \ |
|                                 |         | 20% |         |      | * |
+---------------------------------+---------+-----+---------+------+---+
| > High school graduate          | > 280   | >   | > 395   | >    |   |
|                                 |         | 40% |         |  29% |   |
+---------------------------------+---------+-----+---------+------+---+
| > College+                      | > 277   | >   | > 860   | >    |   |
|                                 |         | 40% |         |  62% |   |
+---------------------------------+---------+-----+---------+------+---+
|                                 |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| [Clinical Features]{.underline} |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| > Cigarette smoking: Current    | > 358   | >   | > 419   | >    | \ |
|                                 |         | 51% |         |  30% | * |
+---------------------------------+---------+-----+---------+------+---+
| Ex                              | > 150   | >   | > 367   | >    |   |
|                                 |         | 21% |         |  27% |   |
+---------------------------------+---------+-----+---------+------+---+
| Never                           | > 194   | >   | > 590   | >    |   |
|                                 |         | 28% |         |  43% |   |
+---------------------------------+---------+-----+---------+------+---+
| > Hypertension (hx)^2^          | > 272   | >   | > 281   | >    | \ |
|                                 |         | 39% |         |  20% | * |
+---------------------------------+---------+-----+---------+------+---+
| > Diabetes (hx)^2^              | > 44    | >   | > 72    | > 5% |   |
|                                 |         |  6% |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| > Primary family history^2^     | > 51    | >   | > 56    | > 5% | \ |
|                                 |         |  9% |         |      | * |
+---------------------------------+---------+-----+---------+------+---+
| > Alcohol use (\>2drinks/day)   | > 95    | >   | > 96    | > 7% | \ |
|                                 |         | 14% |         |      | * |
+---------------------------------+---------+-----+---------+------+---+
| > Cocaine use^3^                | > 12    | >   | > 2     | >    | \ |
|                                 |         |  2% |         | \<1% | * |
+---------------------------------+---------+-----+---------+------+---+
| > Oral contraceptive use^4^ (%  | > 36    | >   | > 74    | >    |   |
| > women)                        |         |  9% |         |  10% |   |
+---------------------------------+---------+-----+---------+------+---+
|                                 |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| > Body mass index (wt/ht2)^2^:  | > 233   | >   | > 391   | >    |   |
| > \<24                          |         | 33% |         |  29% |   |
+---------------------------------+---------+-----+---------+------+---+
| 24-30                           | > 295   | >   | > 659   | >    |   |
|                                 |         | 42% |         |  48% |   |
+---------------------------------+---------+-----+---------+------+---+
| \>30                            | > 169   | >   | > 322   | >    |   |
|                                 |         | 24% |         |  23% |   |
+---------------------------------+---------+-----+---------+------+---+
|                                 |         |     |         |      |   |
+---------------------------------+---------+-----+---------+------+---+
| > URI symptoms (in two weeks)   | > 114   | >   | > 269   | >    |   |
|                                 |         | 17% |         |  20% |   |
+---------------------------------+---------+-----+---------+------+---+

> \*P-value (two-sided)\<.05.
>
> ^1^Among the 709 enrolled subjects, 6 were excluded from the analysis
> (3 subjects had no controls identified; 2 subjects completed
> interviews more than 30 days after their stroke event; and the index
> date for 1 subject could not be determined).
>
> ^2^Missing or uncertain responses: Education (2 cases), hypertension
> (1 control), diabetes (5 cases and 2 controls), primary family history
> (137 cases and 246 controls), body mass index (5 cases and 4
> controls), URI symptoms (39 cases and 54 controls).
>
> ^3^Current use (defined as use on ID or preceding day).
>
> ^4^Use in 3-day window.

Table 3.

# Other Pharmacologic Exposures

# of Case and Control Subjects^1^

+-----------------------------------+-----+---------+-----+---------+---+
|                                   | [   |         | [   |         |   |
|                                   | Cas |         | Con |         |   |
|                                   | es] |         | tro |         |   |
|                                   | {.u |         | ls] |         |   |
|                                   | nde |         | {.u |         |   |
|                                   | rli |         | nde |         |   |
|                                   | ne} |         | rli |         |   |
|                                   |     |         | ne} |         |   |
|                                   | (   |         |     |         |   |
|                                   | n=7 |         | (n  |         |   |
|                                   | 02) |         | =13 |         |   |
|                                   |     |         | 76) |         |   |
+-----------------------------------+-----+---------+-----+---------+---+
| # ASA                             | 79  | 11.3%   | 133 | 9.7%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| NSAIDS                            | 114 | 16.2%   | 292 | 21.2%   | \ |
|                                   |     |         |     |         | * |
+-----------------------------------+-----+---------+-----+---------+---+
| Dextromethorphan hydrobromide     | 25  | 3.6%    | 44  | 3.2%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| ### Sympathomimetic (non-PPA)     |     |         |     |         |   |
+-----------------------------------+-----+---------+-----+---------+---+
| ### Oral preparations^2^          | 58  | 8.3%    | 115 | 8.4%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| > Inhaled preparations            | 11  | 1.6%    | 32  | 2.3%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| > Nasal preparations              | 8   | 1.1%    | 15  | 1.1%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| Stimulants/anorexiants (non-PPA)  | 4   | 0.6%    | 12  | 0.9%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| Oral anticoagulants               | 2   | 0.3%    | 6   | 0.4%    |   |
+-----------------------------------+-----+---------+-----+---------+---+
| Caffeine                          | 49  | 7.0%    | 40  | 2.9%    | \ |
|                                   |     |         |     |         | * |
+-----------------------------------+-----+---------+-----+---------+---+
| Nicotine                          | 9   | 1.3%    | 1   | 0.1%    | \ |
|                                   |     |         |     |         | * |
+-----------------------------------+-----+---------+-----+---------+---+

# ^\*^P-value (two-sided)\<0.05.

# ^1^Use in 3-day window before focal time.

> ^2^Pseudoephedrine hydrochloride, phenylephrine, ephedrine and
> epinephrine contained in medications.

#  

> Table 4.
>
> Phenylpropanolamine (PPA) Exposure
>
> and Risk of Hemorrhagic Stroke

<table style="width:100%;">
<colgroup>
<col style="width: 24%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">Cases</td>
<td colspan="4">Controls</td>
<td colspan="2">Unadjusted</td>
<td colspan="5">Adjusted Estimates<sup>1</sup></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">(n=702)</td>
<td colspan="4">(n=1376)</td>
<td colspan="2">Matched OR</td>
<td colspan="2"><p>Matched</p>
<h2 id="or">OR</h2></td>
<td colspan="2">LCL<sup>2</sup></td>
<td>p-value</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="2">No use<sup>3</sup></td>
<td colspan="2">664</td>
<td colspan="2">94.6%</td>
<td colspan="2">1310</td>
<td colspan="2">95.2%</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td>--</td>
</tr>
<tr class="odd">
<td colspan="2">Any PPA<sup>4</sup></td>
<td colspan="2">27</td>
<td colspan="2">3.8%</td>
<td colspan="2">33</td>
<td colspan="2">2.4%</td>
<td colspan="2">1.67</td>
<td colspan="2">1.49</td>
<td colspan="2">0.93</td>
<td>.084</td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Cough/cold remedy</p>
</blockquote></td>
<td colspan="2">22</td>
<td colspan="2">3.1%</td>
<td colspan="2">32</td>
<td colspan="2">2.3%</td>
<td colspan="2">1.38</td>
<td colspan="2">1.23</td>
<td colspan="2">0.75</td>
<td>.245</td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Appetite suppressant</p>
</blockquote></td>
<td colspan="2">6</td>
<td colspan="2">0.9%</td>
<td colspan="2">1</td>
<td colspan="2">0.1%</td>
<td colspan="2">11.98</td>
<td colspan="2">15.92</td>
<td colspan="2">2.04</td>
<td>.013</td>
</tr>
</tbody>
</table>

######### ^1^Adjusted for smoking, hypertension, race and education.

^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time; 11 cases and 33
controls used PPA between 2 weeks and 3 days before focal time.

^4^One female case used PPA in both a cough/cold remedy and an appetite
suppressant in 3-day window.

##  Table 5.

Recency of PPA Exposure

and Risk of Hemorrhagic Stroke

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 14%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4"></td>
<td colspan="4"></td>
<td colspan="2">Unadjusted</td>
<td colspan="5">Adjusted Estimates<sup>1</sup></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">Cases</td>
<td colspan="4">Controls</td>
<td colspan="2">Matched OR</td>
<td colspan="2"><p>Matched</p>
<h2 id="or-1">OR</h2></td>
<td colspan="2">LCL<sup>2</sup></td>
<td>p-value</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2"><h2 id="section-2" class="unnumbered"></h2></td>
<td colspan="2"><h2 id="section-3" class="unnumbered"></h2></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="2">No use<sup>3</sup></td>
<td colspan="2">664</td>
<td colspan="2">94.6%</td>
<td colspan="2">1310</td>
<td colspan="2">95.2%</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td>--</td>
</tr>
<tr class="odd">
<td colspan="2">Current use<sup>4</sup></td>
<td colspan="2">21</td>
<td colspan="2">3.0%</td>
<td colspan="2">21</td>
<td colspan="2">1.5%</td>
<td colspan="2"><h2 id="section-4">1.98</h2></td>
<td colspan="2"><h2 id="section-5">1.61</h2></td>
<td colspan="2">0.93</td>
<td>.078</td>
</tr>
<tr class="even">
<td colspan="2">First use<sup>5</sup></td>
<td colspan="2">8</td>
<td colspan="2">1.1%</td>
<td colspan="2">5</td>
<td colspan="2">0.4%</td>
<td colspan="2">3.20</td>
<td colspan="2">3.14</td>
<td colspan="2">1.16</td>
<td>.029</td>
</tr>
<tr class="odd">
<td colspan="2">Not-first use</td>
<td colspan="2">13</td>
<td colspan="2">1.9%</td>
<td colspan="2">16</td>
<td colspan="2">1.2%</td>
<td colspan="2">1.62</td>
<td colspan="2">1.20</td>
<td colspan="2">0.61</td>
<td>.329</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Prior use<sup>6</sup></td>
<td colspan="2">6</td>
<td colspan="2">0.9%</td>
<td colspan="2">12</td>
<td colspan="2">0.9%</td>
<td colspan="2"><h2 id="section-6">1.01</h2></td>
<td colspan="2"><h2 id="section-7">1.16</h2></td>
<td colspan="2">0.47</td>
<td>.393</td>
</tr>
</tbody>
</table>

##  {#section-8}

######### ^1^Matched odds ratio adjusted for smoking, hypertension, race and education.

######### ^2^Lower limit of one-sided 95% confidence interval.

> ^3^No PPA use in 2-week period before focal time; 11 cases and 33
> controls used PPA between 2 weeks and 3 days
>
> before focal time.
>
> ^4^Current use is defined as use of any PPA-containing product on
> index date (ID) before focal time or preceding
>
> calendar day. All uses are within 24 hours of Focal Time (FT).
>
> ^5^Current use and no other uses in 2-week period before ID.
>
> ^6^Use of any PPA-containing product 2 or 3 calendar days prior to ID.

##   {#section-9}

Table 6.

PPA Exposed Case Subjects

<table>
<colgroup>
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 19%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td colspan="8">PPA Exposure</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><p>Stroke</p>
<p>Type</p></td>
<td colspan="2">Age</td>
<td><p>HTN</p>
<p>Hx.</p></td>
<td><p>Current</p>
<p>Smoker</p></td>
<td colspan="3"><p>Form</p>
<p>(S=slow;</p>
<p>I=immed</p>
<p>release)</p></td>
<td><p>Dose</p>
<p>in 3 days</p>
<p>(mg)</p></td>
<td colspan="2"><p>Last Dose</p>
<p>(mg)</p></td>
<td colspan="2"><p>Time of</p>
<p>Last Dose</p>
<p>(hrs before FT)</p></td>
</tr>
<tr class="odd">
<td colspan="15">Female Cases</td>
</tr>
<tr class="even">
<td>1.</td>
<td colspan="2">SAH</td>
<td colspan="2">22</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S<sup>1</sup></p>
</blockquote></td>
<td>75</td>
<td colspan="2">75</td>
<td colspan="2">84.0</td>
</tr>
<tr class="odd">
<td>2.</td>
<td colspan="2">SAH</td>
<td colspan="2">26</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>1</sup></p>
</blockquote></td>
<td>600</td>
<td colspan="2">150</td>
<td colspan="2">13.8</td>
</tr>
<tr class="even">
<td>3.</td>
<td colspan="2">SAH</td>
<td colspan="2">30</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>75</td>
<td colspan="2">75</td>
<td colspan="2">1.0</td>
</tr>
<tr class="odd">
<td>4.</td>
<td colspan="2">SAH</td>
<td colspan="2">31</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>890</td>
<td colspan="2">123</td>
<td colspan="2">1.2</td>
</tr>
<tr class="even">
<td>5.</td>
<td colspan="2">SAH</td>
<td colspan="2">31</td>
<td>Y</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>75</td>
<td colspan="2">75</td>
<td colspan="2">8.0</td>
</tr>
<tr class="odd">
<td>6.</td>
<td colspan="2">SAH</td>
<td colspan="2">34</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>300</td>
<td colspan="2">150</td>
<td colspan="2">2.0</td>
</tr>
<tr class="even">
<td>7.</td>
<td colspan="2">SAH</td>
<td colspan="2">38</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>48</td>
<td colspan="2">48</td>
<td colspan="2">43.0</td>
</tr>
<tr class="odd">
<td>8.</td>
<td colspan="2">SAH</td>
<td colspan="2">38</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>1</sup></p>
</blockquote></td>
<td>300</td>
<td colspan="2">75</td>
<td colspan="2">3.8</td>
</tr>
<tr class="even">
<td>9.</td>
<td colspan="2">SAH</td>
<td colspan="2">38</td>
<td>Y</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>1</sup></p>
</blockquote></td>
<td>150</td>
<td colspan="2">75</td>
<td colspan="2">50.0</td>
</tr>
<tr class="odd">
<td>10.</td>
<td colspan="2">SAH</td>
<td colspan="2">42</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>150</td>
<td colspan="2">150</td>
<td colspan="2">1.0</td>
</tr>
<tr class="even">
<td>11.</td>
<td colspan="2">SAH</td>
<td colspan="2">42</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>75</td>
<td colspan="2">75</td>
<td colspan="2">2.0</td>
</tr>
<tr class="odd">
<td>12.</td>
<td colspan="2">SAH</td>
<td colspan="2">44</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>75</td>
<td colspan="2">25</td>
<td colspan="2">13.2</td>
</tr>
<tr class="even">
<td>13.</td>
<td colspan="2">SAH</td>
<td colspan="2">44</td>
<td>Y</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>480</td>
<td colspan="2">48</td>
<td colspan="2">4.5</td>
</tr>
<tr class="odd">
<td>14.</td>
<td colspan="2">SAH</td>
<td colspan="2">46</td>
<td>Y</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>I&amp;S<sup>3</sup></p>
</blockquote></td>
<td>640</td>
<td colspan="2">150</td>
<td colspan="2">9.0</td>
</tr>
<tr class="even">
<td>15.</td>
<td colspan="2">SAH</td>
<td colspan="2">49</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>60</td>
<td colspan="2">20</td>
<td colspan="2">17.5</td>
</tr>
<tr class="odd">
<td>16.</td>
<td colspan="2">IPH</td>
<td colspan="2">25</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>I&amp;S</p>
</blockquote></td>
<td>225</td>
<td colspan="2">75</td>
<td colspan="2">0.5</td>
</tr>
<tr class="even">
<td>17.</td>
<td colspan="2">IPH</td>
<td colspan="2">32</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S<sup>1</sup></p>
</blockquote></td>
<td>225</td>
<td colspan="2">75</td>
<td colspan="2">36.0</td>
</tr>
<tr class="odd">
<td>18.</td>
<td colspan="2">IPH</td>
<td colspan="2">36</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>S</p>
</blockquote></td>
<td>600</td>
<td colspan="2">75</td>
<td colspan="2">0.1</td>
</tr>
<tr class="even">
<td>19.</td>
<td colspan="2">IPH</td>
<td colspan="2">45</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>I<sup>2</sup></p>
</blockquote></td>
<td>75</td>
<td colspan="2">75</td>
<td colspan="2">3.5</td>
</tr>
<tr class="odd">
<td>20.</td>
<td colspan="2">IPH</td>
<td colspan="2">45</td>
<td>-</td>
<td>-</td>
<td colspan="3"><blockquote>
<p>I</p>
</blockquote></td>
<td>13</td>
<td colspan="2">7</td>
<td colspan="2">36.0</td>
</tr>
<tr class="even">
<td>21.</td>
<td colspan="2">IPH</td>
<td colspan="2">48</td>
<td>-</td>
<td>Y</td>
<td colspan="3"><blockquote>
<p>S<sup>2</sup></p>
</blockquote></td>
<td>150</td>
<td colspan="2">150</td>
<td colspan="2">6.0</td>
</tr>
<tr class="odd">
<td colspan="15">Male Cases</td>
</tr>
<tr class="even">
<td colspan="2">22.</td>
<td colspan="2">SAH</td>
<td>20</td>
<td>-</td>
<td colspan="2">Y</td>
<td><blockquote>
<p>I<sup>2</sup></p>
</blockquote></td>
<td colspan="3">150</td>
<td colspan="2">150</td>
<td>1.0</td>
</tr>
<tr class="odd">
<td colspan="2">23.</td>
<td colspan="2">SAH</td>
<td>31</td>
<td>Y</td>
<td colspan="2">Y</td>
<td><blockquote>
<p>I</p>
</blockquote></td>
<td colspan="3">120</td>
<td colspan="2">40</td>
<td>15.0</td>
</tr>
<tr class="even">
<td colspan="2">24.</td>
<td colspan="2">SAH</td>
<td>47</td>
<td>Y</td>
<td colspan="2">-</td>
<td>S</td>
<td colspan="3">75</td>
<td colspan="2">75</td>
<td>54.6</td>
</tr>
<tr class="odd">
<td colspan="2">25.</td>
<td colspan="2">IPH</td>
<td>33</td>
<td>Y</td>
<td colspan="2">Y</td>
<td>S</td>
<td colspan="3">450</td>
<td colspan="2">50</td>
<td>5.5</td>
</tr>
<tr class="even">
<td colspan="2">26.</td>
<td colspan="2">IPH</td>
<td>42</td>
<td>Y</td>
<td colspan="2">-</td>
<td><blockquote>
<p>I</p>
</blockquote></td>
<td colspan="3">160</td>
<td colspan="2">40</td>
<td>1.5</td>
</tr>
<tr class="odd">
<td colspan="2">27.</td>
<td colspan="2">IPH</td>
<td>47</td>
<td>Y</td>
<td colspan="2">Y</td>
<td>S</td>
<td colspan="3">225</td>
<td colspan="2">75</td>
<td>18.0</td>
</tr>
</tbody>
</table>

> ^1^Appetite suppressant use.
>
> ^2^First dose use.
>
> ^3^Subject used both appetite suppressant and cough/cold remedy.

Table 7.

PPA Exposed Control Subjects

+----+-----+-----+--------+---------+---------+------+--------------+
|    |     |     |        | PPA     |         |      |              |
|    |     |     |        | E       |         |      |              |
|    |     |     |        | xposure |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
|    | Age | HTN | C      | Form    | Dose    | Last | Time of      |
|    |     |     | urrent |         |         | Dose |              |
|    |     | Hx. |        | (       | in 3    |      | Last Dose    |
|    |     |     | Smoker | S=slow; | days    | (mg) |              |
|    |     |     |        |         |         |      | (hrs before  |
|    |     |     |        | I=immed | (mg)    |      | FT)          |
|    |     |     |        |         |         |      |              |
|    |     |     |        | r       |         |      |              |
|    |     |     |        | elease) |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| Fe |     |     |        |         |         |      |              |
| ma |     |     |        |         |         |      |              |
| le |     |     |        |         |         |      |              |
| Co |     |     |        |         |         |      |              |
| nt |     |     |        |         |         |      |              |
| ro |     |     |        |         |         |      |              |
| ls |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 1  | 39  | \-  | Y      | > S     | 150     | 75   | 2.5          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 2  | 25  | \-  | \-     | > I^1^  | 150     | 75   | 9.0          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 3  | 33  | \-  | \-     | > I     | 75      | 37   | 2.0          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 4  | 43  | \-  | Y      | > S     | 300     | 75   | 13.5         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 5  | 43  | \-  | Y      | > I     | 50      | 50   | 57.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 6  | 40  | Y   | Y      | > I     | 175     | 25   | 0.6          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 7  | 44  | \-  | \-     | > S^2^  | 150     | 75   | 54.8         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 8  | 42  | Y   | \-     | > I     | 225     | 75   | 24.5         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 9  | 44  | \-  | Y      | > S     | 525     | 75   | 4.0          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 10 | 34  | Y   | \-     | > I     | 225     | 25   | 24.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 11 | 43  | Y   | \-     | > S     | 75      | 75   | 3.0          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 12 | 40  | \-  | \-     | > S     | 150     | 75   | 75.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 13 | 27  | \-  | Y      | > S     | 225     | 75   | 20.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 14 | 42  | Y   | \-     | > S     | 600     | 75   | 3.0          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 15 | 33  | Y   | \-     | > S     | 450     | 150  | 14.5         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 16 | 40  | \-  | Y      | > I     | 80      | 40   | 9.5          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 17 | 38  | \-  | \-     | > I^1^  | 37      | 37   | 40.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 18 | 36  | \-  | Y      | > S     | 75      | 75   | 14.3         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 19 | 41  | \-  | \-     | > S^1^  | 75      | 75   | 5.8          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 20 | 30  | \-  | Y      | > I^1^  | 825     | 75   | 2.5          |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| Ma |     |     |        |         |         |      |              |
| le |     |     |        |         |         |      |              |
| Co |     |     |        |         |         |      |              |
| nt |     |     |        |         |         |      |              |
| ro |     |     |        |         |         |      |              |
| ls |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 21 | 47  | \-  | \-     | > I     | 96      | 48   | 42.5         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 22 | 48  | Y   | Y      | > S     | 150     | 75   | 55.0         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 23 | 37  | \-  | Y      | > I     | 50      | 12   | 38.5         |
| \. |     |     |        |         |         |      |              |
+----+-----+-----+--------+---------+---------+------+--------------+
| 24 | 47  | \-  | \-     | > S     | 225     | 75   | 23.8         |
+----+-----+-----+--------+---------+---------+------+--------------+
| 25 | 34  | \-  | \-     | > I^1^  | 120     | 40   | 4.0          |
+----+-----+-----+--------+---------+---------+------+--------------+
| 26 | 48  | Y   | Y      | > I     | 25      | 25   | 77.5         |
+----+-----+-----+--------+---------+---------+------+--------------+
| 27 | 30  | \-  | \-     | > I     | 300     | 75   | 28.0         |
+----+-----+-----+--------+---------+---------+------+--------------+
| 28 | 32  | \-  | \-     | > S     | 75      | 75   | 70.2         |
+----+-----+-----+--------+---------+---------+------+--------------+
| 29 | 36  | \-  | \-     | > S     | 525     | 75   | 6.2          |
+----+-----+-----+--------+---------+---------+------+--------------+
| 30 | 33  | \-  | \-     | > S     | 75      | 75   | 38.1         |
+----+-----+-----+--------+---------+---------+------+--------------+
| 31 | 28  | \-  | Y      | > I     | 25      | 25   | 1.0          |
+----+-----+-----+--------+---------+---------+------+--------------+
| 32 | 38  | \-  | \-     | > I     | 175     | 25   | 3.5          |
+----+-----+-----+--------+---------+---------+------+--------------+
| 33 | 43  | \-  | \-     | > S     | 135     | 45   | 48.0         |
+----+-----+-----+--------+---------+---------+------+--------------+

> ^1^First dose use.
>
> ^2^Appetite suppressant use.

#   {#section-10}

[APPENDIX A]{.underline}

HSP Participating Hospitals

+----------------------------------+-----------------------------------+
| ### [Connecticut                 | [Cincinnati, Ohio/Northern        |
|  and Massachusetts]{.underline}  | Kentucky]{.underline}             |
+----------------------------------+-----------------------------------+
| ## Backus                        | ## Bethesda North                 |
+----------------------------------+-----------------------------------+
| > Baystate                       | > Bethesda Oak                    |
+----------------------------------+-----------------------------------+
| > Bridgeport                     | > Deaconess                       |
+----------------------------------+-----------------------------------+
| > Danbury                        | > Good Samaritan                  |
+----------------------------------+-----------------------------------+
| > Gaylord                        | > Our Lady of Mercy/Anderson      |
+----------------------------------+-----------------------------------+
| > Greenwich                      | > Our Lady of Mercy/Clermont      |
+----------------------------------+-----------------------------------+
| > Griffin                        | > Our Lady of Mercy/Fairfield     |
+----------------------------------+-----------------------------------+
| > Hartford                       | > Providence                      |
+----------------------------------+-----------------------------------+
| > Hospital for Special Care      | > St. Elizabeth/North             |
+----------------------------------+-----------------------------------+
| > Lawrence Memorial              | > St. Elizabeth/South             |
+----------------------------------+-----------------------------------+
| > Manchester                     | > St. Francis/St. George          |
+----------------------------------+-----------------------------------+
| > Middlesex                      | > St. Luke/East                   |
+----------------------------------+-----------------------------------+
| > Mount Sinai                    | > St. Luke/West                   |
+----------------------------------+-----------------------------------+
| > New Britain                    | > The Christ                      |
+----------------------------------+-----------------------------------+
| > Norwalk                        | > The Jewish                      |
+----------------------------------+-----------------------------------+
| > Rehabilitation Hospital of     | > U. Cincinnati, Medical Center   |
| > Conn.                          |                                   |
+----------------------------------+-----------------------------------+
| > St. Francis                    | > Veterans Adm.                   |
+----------------------------------+-----------------------------------+
| > St. Joseph                     | ### [Provi                        |
|                                  | dence, Rhode Island]{.underline}  |
+----------------------------------+-----------------------------------+
| > St. Mary                       | # Miriam                          |
+----------------------------------+-----------------------------------+
| > St. Raphael                    | > Rhode Island                    |
+----------------------------------+-----------------------------------+
| > St. Vincent                    | ### [Houston, Texas]{.underline}  |
+----------------------------------+-----------------------------------+
| > Stamford                       | ###  Hermann                      |
+----------------------------------+-----------------------------------+
| > Waterbury                      | ###  {#section-11}                |
+----------------------------------+-----------------------------------+
| > Yale-New Haven                 | ###  {#section-12}                |
+----------------------------------+-----------------------------------+

#### [Appendix B]{.underline}

> Case Subjects Excluded after Enrollment:
>
> Overall and by Site

+--------------------------------------+-----+-----+-----+-----+-----+
|                                      | To  | CT  | OH  | TX  | RI  |
|                                      | tal |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| Case subjects enrolled               | 746 | 268 | 233 | 136 | 109 |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| Less: Case subjects excluded after   | 38  | 16  | 6   | 7   | 9   |
| review                               |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Ineligible events                  | 32  | 13  | 4   | 6   | 9   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > No evidence for hemorrhage         | 19  | 7   | 2   | 3   | 7   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Hemorrhage due to trauma           | 6   | 3   | 0   | 1   | 2   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Venous thrombosis                  | 4   | 2   | 1   | 1   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Subdural hemorrhage                | 2   | 1   | 0   | 1   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > TPA induced bleed                  | 1   | 0   | 1   | 0   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Ineligible subjects                | 6   | 3   | 2   | 1   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > History of AVM or tumor            | 4   | 1   | 2   | 1   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > Event \> 72 hrs. after admission   | 1   | 1   | 0   | 0   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
| > History of SAH                     | 1   | 1   | 0   | 0   | 0   |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| Equals: Eligible case subjects       | 708 | 252 | 227 | 129 | 100 |
| enrolled                             |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| Less: Other exclusions               | 6   | 3   | 1   | 1   | 1   |
+--------------------------------------+-----+-----+-----+-----+-----+
|                                      |     |     |     |     |     |
+--------------------------------------+-----+-----+-----+-----+-----+
| Equals: Final case group             | 702 | 249 | 226 | 128 | 99  |
+--------------------------------------+-----+-----+-----+-----+-----+

> Legend: Appendix B displays the number of case subjects enrolled
> overall and by site (CT=Connecticut, OH=Cincinnati, Ohio, TX=Houston,
> Texas, RI=Providence, Rhode Island). Reasons for exclusions of
> enrolled case subject following validation review are listed. Six
> eligible and enrolled case subjects were excluded from the final case
> group for the following reasons: no matched controls identified (3
> subjects), interview date for case subject was over 30 days from index
> date (2 subjects), and index date for stroke event was uncertain
>
> (1 subject).

# [Appendix C]{.underline} 

# PPA Exposures: Matched Format

  ------------------ ---------- ----- ----- -- ---------- ----- ----- -- ---------- ---- ------
                     All                       Women                     Men             
                     Subjects                                                            

  Any PPA            No.                       No.                       No.             
                     Controls                  Controls                  Controls        
                     Exposed                   Exposed                   Exposed         

                     0          1     2        0          1     2        0          1    2

  Case: Exposed      25         2     0        20         1     0        5          1    0

  Not exposed        646        27    2        344        17    1        302        10   1

  Cough/cold remedy                                                                      

  Case: Exposed      21         1     0        16         0     0        5          1    0

  Not exposed        651        27    2        349        17    1        302        10   1

  Appetite                                                                               
  suppressant                                                                            

  Case: Exposed      6          0     0        6          0     0        0          0    0

  Not exposed        695        1     0        376        1     0        319        0    0
  ------------------ ---------- ----- ----- -- ---------- ----- ----- -- ---------- ---- ------

#  {#section-13}

# Legend: Appendix C displays the number of case/control sets overall and by gender according to the exposure status of the case subject and number of matched controls exposed to any PPA in the 3-day window and to PPA in cough/cold remedy and appetite suppressants. (Note: Except for 28 cases with one matched control, each case subject was matched to two control subjects. All 16 female and 12 male case-control pairs were concordant as 

# not-exposed to any PPA and are included in the lower left entries in each table.) 

[Appendix D]{.underline}

Analyses Stratified by Gender: Phenylpropanolamine (PPA) Exposure

and Risk of Hemorrhagic Stroke

###### WOMEN

+----------------+----+-----+----+-----+----------+------+-----+----+
|                | C  |     | Co |     | Un       | Adju |     |    |
|                | as |     | nt |     | adjusted | sted |     |    |
|                | es |     | ro |     |          | Esti |     |    |
|                |    |     | ls |     |          | mate |     |    |
|                |    |     |    |     |          | s^1^ |     |    |
+----------------+----+-----+----+-----+----------+------+-----+----+
|                | (  |     | (  |     | Matched  | Mat  | LCL | p  |
|                | n= |     | n= |     |          | ched | ^2^ | -v |
|                | 38 |     | 75 |     | OR       |      |     | al |
|                | 3) |     | 0) |     |          | #    |     | ue |
|                |    |     |    |     |          | # OR |     |    |
|                |    |     |    |     |          |  {#o |     |    |
|                |    |     |    |     |          | r-2} |     |    |
+----------------+----+-----+----+-----+----------+------+-----+----+
|                | N  | \%  | N  | \%  |          |      |     |    |
|                | o. |     | o. |     |          |      |     |    |
+----------------+----+-----+----+-----+----------+------+-----+----+
| No use^3^      | 3  | 92  | 7  | 95  | \--      | \--  | \-- | \  |
|                | 55 | .7% | 13 | .1% |          |      |     | -- |
+----------------+----+-----+----+-----+----------+------+-----+----+
| Any PPA^4^     | 21 | 5   | 20 | 2   | 2.15     | 1.98 | 1   | .0 |
|                |    | .5% |    | .7% | (p=.014) |      | .12 | 24 |
+----------------+----+-----+----+-----+----------+------+-----+----+
| > Cough/cold   | 16 | 4   | 19 | 2   | 1.70     | 1.54 | 0   | .1 |
| > remedy       |    | .2% |    | .5% | (p=.089) |      | .85 | 16 |
+----------------+----+-----+----+-----+----------+------+-----+----+
| > Appetite     | 6  | 1   | 1  | 0   | 12.19    | 1    | 2   | .0 |
| > suppressant  |    | .6% |    | .1% | (p=.006) | 6.58 | .22 | 11 |
+----------------+----+-----+----+-----+----------+------+-----+----+

MEN

<table style="width:100%;">
<colgroup>
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 7%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="4">Cases</td>
<td colspan="4">Controls</td>
<td colspan="2">Unadjusted</td>
<td colspan="5">Adjusted Estimates<sup>1</sup></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4">(n=319)</td>
<td colspan="4">(n=626)</td>
<td colspan="2"><p>Matched</p>
<p>OR</p></td>
<td colspan="2"><p>Matched</p>
<h2 id="or-3">OR</h2></td>
<td colspan="2">LCL<sup>2</sup></td>
<td>p-value</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2">No.</td>
<td colspan="2">%</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="2">No use<sup>3</sup></td>
<td colspan="2">309</td>
<td colspan="2">96.9%</td>
<td colspan="2">597</td>
<td colspan="2">95.4%</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td>--</td>
</tr>
<tr class="odd">
<td colspan="2">Any PPA</td>
<td colspan="2">6</td>
<td colspan="2">1.9%</td>
<td colspan="2">13</td>
<td colspan="2">2.1%</td>
<td colspan="2">0.90 (p=.529)</td>
<td colspan="2">0.62</td>
<td colspan="2">--</td>
<td>.203</td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Cough/cold remedy</p>
</blockquote></td>
<td colspan="2">6</td>
<td colspan="2">1.9%</td>
<td colspan="2">13</td>
<td colspan="2">2.1%</td>
<td colspan="2">0.90 (p=.529)</td>
<td colspan="2">0.62</td>
<td colspan="2">--</td>
<td>.203</td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Appetite suppressant</p>
</blockquote></td>
<td colspan="2">0</td>
<td colspan="2">0.0%</td>
<td colspan="2">0</td>
<td colspan="2">0.0%</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td colspan="2">--</td>
<td>--</td>
</tr>
</tbody>
</table>

######### ^1^Adjusted for smoking, hypertension, race and education.

^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time.

^4^One female case used PPA in both a cough/cold remedy and an appetite
suppressant in 3-day window.

[Appendix D, continued]{.underline}

Analyses Stratified by Gender: Recency of PPA Exposure

and Risk of Hemorrhagic Stroke

####### WOMEN

+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | C  |     | Co  |     | Un       | Adj   |     |    |
|             | as |     | ntr |     | adjusted | usted |     |    |
|             | es |     | ols |     |          | Es    |     |    |
|             |    |     |     |     |          | timat |     |    |
|             |    |     |     |     |          | es^1^ |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | (  |     | (   |     | Matched  | Ma    | LCL | p  |
|             | n= |     | n=7 |     |          | tched | ^2^ | -v |
|             | 38 |     | 50) |     | OR       |       |     | al |
|             | 3) |     |     |     |          | ##    |     | ue |
|             |    |     |     |     |          | OR {# |     |    |
|             |    |     |     |     |          | or-4} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | N  | \%  | No. | \%  |          |       |     |    |
|             | o. |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| No use^3^   | 3  | 92  | 713 | 95  | \--      | \--   | \-- | \  |
|             | 55 | .7% |     | .1% |          |       |     | -- |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Current     | 16 | 4   | 16  | 2   | ## 1.97  | #     | 0   | .0 |
| use^4^      |    | .2% |     | .1% | (p=.041) | # 1.6 | .91 | 84 |
|             |    |     |     |     |          | 7 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-14} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| First       | 7  | 1   | 4   | 0   | 3.50     | 3.13  | 1   | .0 |
| use^5^      |    | .8% |     | .5% | (p=.039) |       | .05 | 42 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Not-first   | 9  | 2   | 12  | 1   | 1.50     | 1.24  | 0   | .3 |
| use         |    | .3% |     | .6% | (p=.241) |       | .59 | 17 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             |    |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Prior       | 5  | 1   | 4   | 0   | ## 2.61  | #     | 1   | .0 |
| use^6^      |    | .3% |     | .5% | (p=.132) | # 3.8 | .05 | 43 |
|             |    |     |     |     |          | 2 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-15} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+

##  {#section-16}

####### MEN

+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | C  |     | Co  |     | Un       | Adj   |     |    |
|             | as |     | ntr |     | adjusted | usted |     |    |
|             | es |     | ols |     |          | Es    |     |    |
|             |    |     |     |     |          | timat |     |    |
|             |    |     |     |     |          | es^1^ |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | (  |     | (   |     | Matched  | Ma    | LCL | p  |
|             | n= |     | n=6 |     |          | tched | ^2^ | -v |
|             | 31 |     | 26) |     | OR       |       |     | al |
|             | 9) |     |     |     |          | ##    |     | ue |
|             |    |     |     |     |          | OR {# |     |    |
|             |    |     |     |     |          | or-5} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | N  | \%  | No. | \%  |          |       |     |    |
|             | o. |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| No use^3^   | 3  | 96  | 597 | 95  | ## \     | ## \- | \-- | \  |
|             | 09 | .9% |     | .4% | -- {#sec | - {#s |     | -- |
|             |    |     |     |     | tion-17} | ectio |     |    |
|             |    |     |     |     |          | n-18} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Current     | 5  | 1   | 5   | 0   | ## 2.03  | #     | 0   | .3 |
| use^4^      |    | .6% |     | .8% | (p=.237) | # 1.2 | .34 | 85 |
|             |    |     |     |     |          | 6 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-19} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| First       | 1  | 0   | 1   | 0   | 2.00     | 2.95  | 0   | .2 |
| use^5^      |    | .3% |     | .2% | (p=.556) |       | .24 | 41 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Not-first   | 4  | 1   | 4   | 0   | 2.06     | 0.95  | \-- | .4 |
| use         |    | .2% |     | .6% | (p=.285) |       |     | 79 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             |    |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Prior       | 1  | 0   | 8   | 1   | ## 0.25  | #     | \-- | .0 |
| use^6^      |    | .3% |     | .3% | (p=.140) | # 0.2 |     | 98 |
|             |    |     |     |     |          | 5 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-20} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+

######### ^1^Matched odds ratio adjusted for smoking, hypertension, race and education.

######### ^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time.

^4^Use of any PPA-containing product on index date (ID) before focal
time or preceding calendar day.

^5^Current use and no other uses in 2-week period before ID.

^6^Use of any PPA-containing product 2 or 3 calendar days prior to ID.

##  {#section-21}

[Appendix E]{.underline}

Analyses Stratified by Sentinel Symptoms: Phenylpropanolamine (PPA)
Exposure

and Risk of Hemorrhagic Stroke

######## NO SENTINEL SYMPTOMS

+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | C  |     | Co |     | Una     | Adju |     |     |
|                | as |     | nt |     | djusted | sted |     |     |
|                | es |     | ro |     |         | Esti |     |     |
|                |    |     | ls |     |         | mate |     |     |
|                |    |     |    |     |         | s^1^ |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | (  |     | (n |     | Matched | Mat  | LCL | p   |
|                | n= |     | =1 |     |         | ched | ^2^ | -va |
|                | 54 |     | 07 |     | OR      |      |     | lue |
|                | 8) |     | 5) |     |         | #    |     |     |
|                |    |     |    |     |         | # OR |     |     |
|                |    |     |    |     |         |  {#o |     |     |
|                |    |     |    |     |         | r-6} |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | N  | \%  | N  | \%  |         |      |     |     |
|                | o. |     | o. |     |         |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| No use^3^      | 5  | 94  | 10 | 95  | \--     | \--  | \-- | \-- |
|                | 19 | .7% | 22 | .1% |         |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| Any PPA^4^     | 20 | 3   | 26 | 2   | 1.55    | 1.33 | 0   | .   |
|                |    | .6% |    | .4% | (       |      | .77 | 194 |
|                |    |     |    |     | p=.104) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| > Cough/cold   | 17 | 3   | 25 | 2   | 1.35    | 1.12 | 0   | .   |
| > remedy       |    | .1% |    | .3% | (       |      | .64 | 371 |
|                |    |     |    |     | p=.221) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| > Appetite     | 4  | 0   | 1  | 0   | 7.96    | 1    | 1   | .   |
| > suppressant  |    | .7% |    | .1% | (       | 2.10 | .39 | 029 |
|                |    |     |    |     | p=.046) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+

SENTINEL SYMPTOMS PRESENT OR UNCERTAIN

+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | C  |     | Co |     | Una     | Adju |     |     |
|                | as |     | nt |     | djusted | sted |     |     |
|                | es |     | ro |     |         | Esti |     |     |
|                |    |     | ls |     |         | mate |     |     |
|                |    |     |    |     |         | s^1^ |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | (  |     | (  |     | Matched | Mat  | LCL | p   |
|                | n= |     | n= |     |         | ched | ^2^ | -va |
|                | 15 |     | 30 |     | OR      |      |     | lue |
|                | 4) |     | 1) |     |         | #    |     |     |
|                |    |     |    |     |         | # OR |     |     |
|                |    |     |    |     |         |  {#o |     |     |
|                |    |     |    |     |         | r-7} |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
|                | N  | \%  | N  | \%  |         |      |     |     |
|                | o. |     | o. |     |         |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| No use^3^      | 1  | 94  | 2  | 95  | \--     | \--  | \-- | \-- |
|                | 45 | .2% | 88 | .7% |         |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| Any PPA        | 7  | 4   | 7  | 2   | 2.13    | 2.19 | 0   | .   |
|                |    | .6% |    | .3% | (       |      | .80 | 099 |
|                |    |     |    |     | p=.141) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| > Cough/cold   | 5  | 3   | 7  | 2   | 1.48    | 1.71 | 0   | .   |
| > remedy       |    | .2% |    | .3% | (       |      | .58 | 206 |
|                |    |     |    |     | p=.365) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+
| > Appetite     | 2  | 1   | 0  | 0   | 4.83    | \--  | \-- | \-- |
| > suppressant  |    | .3% |    | .0% | (       |      |     |     |
|                |    |     |    |     | p=.111) |      |     |     |
+----------------+----+-----+----+-----+---------+------+-----+-----+

######### ^1^Matched odds ratio adjusted for smoking, hypertension, race and education.

^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time.

^4^One case used PPA in both a cough/cold remedy and an appetite
suppressant in 3-day window.

[Appendix E, continued]{.underline}

Analyses Stratified by Sentinel Symptoms: Recency of PPA Exposure

and Risk of Hemorrhagic Stroke

####### NO SENTINEL SYMPTOMS

+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | C  |     | Co  |     | Un       | Adj   |     |    |
|             | as |     | ntr |     | adjusted | usted |     |    |
|             | es |     | ols |     |          | Es    |     |    |
|             |    |     |     |     |          | timat |     |    |
|             |    |     |     |     |          | es^1^ |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | (  |     | (n  |     | Matched  | Ma    | LCL | p  |
|             | n= |     | =10 |     |          | tched | ^2^ | -v |
|             | 54 |     | 75) |     | OR       |       |     | al |
|             | 8) |     |     |     |          | ##    |     | ue |
|             |    |     |     |     |          | OR {# |     |    |
|             |    |     |     |     |          | or-8} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | N  | \%  | No. | \%  |          |       |     |    |
|             | o. |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| No use^3^   | 5  | 94  | 1   | 95  |          |       |     |    |
|             | 19 | .7% | 022 | .1% |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Current     | 17 | 3   | 18  | 1   | ## 1.85  | #     | 0   | .1 |
| use4        |    | .1% |     | .7% | (p=.054) | # 1.4 | .78 | 69 |
|             |    |     |     |     |          | 2 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-22} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| First use5  | 6  | 1   | 4   | 0   | 3.00     | 3.34  | 1   | .0 |
|             |    | .1% |     | .4% | (p=.077) |       | .08 | 40 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Not-first   | 11 | 2   | 14  | 1   | 1.55     | 1.02  | 0   | .4 |
| use         |    | .1% |     | .3% | (p=.196) |       | .50 | 79 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             |    |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Prior use6  | 3  | 0   | 8   | 0   | ## 0.76  | #     | \-- | .4 |
|             |    | .6% |     | .7% | (p=.481) | # 0.9 |     | 89 |
|             |    |     |     |     |          | 8 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-23} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+

####### SENTINEL SYMPTOMS PRESENT OR UNCERTAIN

+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | C  |     | Co  |     | Un       | Adj   |     |    |
|             | as |     | ntr |     | adjusted | usted |     |    |
|             | es |     | ols |     |          | Es    |     |    |
|             |    |     |     |     |          | timat |     |    |
|             |    |     |     |     |          | es^1^ |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | (  |     | (   |     | Matched  | Ma    | LCL | p  |
|             | n= |     | n=3 |     |          | tched | ^2^ | -v |
|             | 15 |     | 01) |     | OR       |       |     | al |
|             | 4) |     |     |     |          | ##    |     | ue |
|             |    |     |     |     |          | OR {# |     |    |
|             |    |     |     |     |          | or-9} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | N  | \%  | No. | \%  |          |       |     |    |
|             | o. |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| No use^3^   | 1  | 94  | 288 | 95  | \--      | \--   | \-- | \  |
|             | 45 | .2% |     | .7% |          |       |     | -- |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Current     | 4  | 2   | 3   | 1   | ## 2.67  | #     | 0   | .0 |
| use^4^      |    | .6% |     | .0% | (p=.173) | # 2.9 | .76 | 96 |
|             |    |     |     |     |          | 5 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-24} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| First       | 2  | 1   | 1   | 0   | 4.00     | 2.70  | 0   | .2 |
| use^5^      |    | .3% |     | .3% | (p=.259) |       | .34 | 15 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Not-first   | 2  | 1   | 2   | 0   | 2.06     | 3.17  | 0   | .1 |
| use         |    | .3% |     | .7% | (p=.395) |       | .53 | 45 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             |    |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Prior       | 3  | 2   | 4   | 1   | ## 1.53  | #     | 0   | .3 |
| use^6^      |    | .0% |     | .3% | (p=.418) | # 1.5 | .36 | 18 |
|             |    |     |     |     |          | 1 {#s |     |    |
|             |    |     |     |     |          | ectio |     |    |
|             |    |     |     |     |          | n-25} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+

######### ^1^Matched odds ratio adjusted for smoking, hypertension, race and education.

######### ^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time.

^4^Use of any PPA-containing product on index date (ID) before focal
time or preceding calendar day.

^5^Current use and no other uses in 2-week period before ID.

^6^Use of any PPA-containing product 2 or 3 calendar days prior to ID.

[Appendix F]{.underline}

Analyses using Alternate Index Date: Phenylpropanolamine (PPA) Exposure

and Risk of Hemorrhagic Stroke

+----------------+----+-----+----+-----+----------+------+----+-----+
|                | C  |     | Co |     | Un       | Adju |    |     |
|                | as |     | nt |     | adjusted | sted |    |     |
|                | es |     | ro |     |          | Esti |    |     |
|                |    |     | ls |     |          | mate |    |     |
|                |    |     |    |     |          | s^1^ |    |     |
+----------------+----+-----+----+-----+----------+------+----+-----+
|                | (  |     | (n |     | Matched  | Mat  | LC | p   |
|                | n= |     | =1 |     |          | ched | L^ | -va |
|                | 70 |     | 37 |     | OR       |      | 2^ | lue |
|                | 2) |     | 6) |     |          | ##   |    |     |
|                |    |     |    |     |          |  OR  |    |     |
|                |    |     |    |     |          | {#or |    |     |
|                |    |     |    |     |          | -10} |    |     |
+----------------+----+-----+----+-----+----------+------+----+-----+
|                | N  | \%  | N  | \%  |          |      |    |     |
|                | o. |     | o. |     |          |      |    |     |
+----------------+----+-----+----+-----+----------+------+----+-----+
| No use^3^      | 6  | 94  | 13 | 95  | \--      | \--  | \  | \-- |
|                | 63 | .4% | 10 | .2% |          |      | -- |     |
+----------------+----+-----+----+-----+----------+------+----+-----+
| Any PPA^4^     | 28 | 4   | 33 | 2   | 1.74     | 1.57 | 0. | .   |
|                |    | .0% |    | .4% | (p=.028) |      | 98 | 059 |
+----------------+----+-----+----+-----+----------+------+----+-----+
| > Cough/cold   | 23 | 3   | 32 | 2   | 1.45     | 1.31 | 0. | .   |
| > remedy       |    | .3% |    | .3% | (p=.122) |      | 80 | 186 |
+----------------+----+-----+----+-----+----------+------+----+-----+
| > Appetite     | 6  | 0   | 1  | 0   | 12.01    | 1    | 2. | .   |
| > suppressant  |    | .8% |    | .1% | (p=.007) | 6.02 | 06 | 013 |
+----------------+----+-----+----+-----+----------+------+----+-----+

Analyses using Alternate Index Date: Recency of PPA Exposure

and Risk of Hemorrhagic Stroke

+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | C  |     | Co  |     | Un       | Adj   |     |    |
|             | as |     | ntr |     | adjusted | usted |     |    |
|             | es |     | ols |     |          | Es    |     |    |
|             |    |     |     |     |          | timat |     |    |
|             |    |     |     |     |          | es^1^ |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | (  |     | (n  |     | Matched  | Ma    | LCL | p  |
|             | n= |     | =13 |     |          | tched | ^2^ | -v |
|             | 70 |     | 76) |     | OR       |       |     | al |
|             | 2) |     |     |     |          | ## O  |     | ue |
|             |    |     |     |     |          | R {#o |     |    |
|             |    |     |     |     |          | r-11} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             | N  | \%  | No. | \%  |          |       |     |    |
|             | o. |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| No use^3^   | 6  | 94  | 1   | 95  | \--      | \--   | \-- | \  |
|             | 63 | .4% | 310 | .2% |          |       |     | -- |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Current     | 22 | 3   | 20  | 1   | ## [2.   | #     | 1   | .0 |
| use^5^      |    | .1% |     | .4% | 18 (p=.0 | # 1.7 | .03 | 42 |
|             |    |     |     |     | 10)]{.sm | 8 {#s |     |    |
|             |    |     |     |     | allcaps} | ectio |     |    |
|             |    |     |     |     |          | n-26} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| First       | 9  | 1   | 4   | 0   | 4.50     | 4.49  | 1   | .0 |
| use^6^      |    | .3% |     | .3% | (p=.009) |       | .58 | 09 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Not-first   | 13 | 1   | 16  | 1   | 1.62     | 1.20  | 0   | .3 |
| use         |    | .8% |     | .2% | (p=.141) |       | .61 | 26 |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
|             |    |     |     |     |          |       |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+
| Prior       | 6  | 0   | 13  | 0   | ## [0.   | #     | 0   | .4 |
| use^7^      |    | .8% |     | .9% | 94 (p=.5 | # 1.0 | .45 | 44 |
|             |    |     |     |     | 58)]{.sm | 8 {#s |     |    |
|             |    |     |     |     | allcaps} | ectio |     |    |
|             |    |     |     |     |          | n-27} |     |    |
+-------------+----+-----+-----+-----+----------+-------+-----+----+

######### ^1^Adjusted for smoking, hypertension, race and education.

^2^Lower limit of one-sided 95% confidence interval.

^3^No PPA use in 2-week period before focal time.

^4^One female case used PPA in both a cough/cold remedy and an appetite
suppressant in 3-day window.

^5^Use of any PPA-containing product on index date (ID) before focal
time or preceding calendar day.

^6^Current use and no other uses in 2-week period before ID.

^7^Use of any PPA-containing product 2 or 3 calendar days prior to ID.

## [Appendix G]{.underline}

> Gender and Age Distribution
>
> of PPA-Exposed and Non-Exposed in the HSP

  -------------------- ------------------- ----------------- ------------------- ----------------- ------------------- ----------------- ------------------- -----------------
                       Case Subjects                                                               Control Subjects                                          

                       Exposed                               Not Exposed                           Exposed                               Not Exposed         

                       [No.]{.underline}   [%]{.underline}   [No.]{.underline}   [%]{.underline}   [No.]{.underline}   [%]{.underline}   [No.]{.underline}   [%]{.underline}

  Any PPA                                                                                                                                                    

  Women                21                  78%               362                 54%               20                  61%               730                 54%

  Men                  6                   22%               313                 46%               13                  39%               613                 46%

                                                                                                                                                             

  Age \< 40            15                  56%               281                 42%               17                  52%               575                 43%

  Age [\>]{.underline} 12                  44%               394                 58%               16                  48%               768                 57%
  40                                                                                                                                                         

                                                                                                                                                             

  Cough/cold remedy                                                                                                                                          

  Women                16                  73%               367                 54%               19                  59%               731                 54%

  Men                  6                   27%               313                 46%               13                  41%               613                 46%

                                                                                                                                                             

  Age \< 40            10                  45%               286                 42%               17                  53%               575                 43%

  Age [\>]{.underline} 12                  55%               394                 58%               15                  47%               769                 57%
  40                                                                                                                                                         

                                                                                                                                                             

  Appetite suppressant                                                                                                                                       

  Women                6                   100%              377                 54%               1                   100%              749                 54%

  Men                  0                   0%                319                 46%               0                   0%                626                 46%

                                                                                                                                                             

  Age \< 40            5                   83%               291                 42%               0                   0%                592                 43%

  Age [\>]{.underline} 1                   17%               405                 58%               1                   100%              783                 57%
  40                                                                                                                                                         
  -------------------- ------------------- ----------------- ------------------- ----------------- ------------------- ----------------- ------------------- -----------------

# Legend: Appendix G displays the number and percentage of case and control subjects who were exposed and not-exposed to PPA (definite/probable uses) in the 3-day window by gender and age group. Data are displayed for any 

# PPA-containing product and for PPA in cough/cold remedy and appetite suppressants.