The impact of oral phenylpropanolamine on blood pressure: a ... - Nature

Journal of Human Hypertension (2005) 19, 643–652 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

The impact of oral phenylpropanolamine on blood pressure: a meta-analysis and review of the literature SM Salerno1, JL Jackson2 and EP Berbano3 1

Department of Medicine, Tripler Army Medical Center, Honolulu, HI, USA; 2Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 3Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA

Oral phenylpropanolamine is commonly used to treat congestion and obesity. Clinicians often wonder what effect it has on blood pressure and whether they are safe in hypertensive patients. The purpose of our systematic review was to assess whether these drugs cause clinically meaningful elevations in pulse or blood pressure. English-language, randomized, placebo-controlled trials of oral phenylpropanolamine in adults with extractable data on pulse or blood pressure were studied. MEDLINE (1966–2003), Embase, the Cohcrane library and reviewed article references were used as sources. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate data were extracted. Additional extracted data included demographics, year, study design, study duration, drug dose and frequency, duration of washout and country. Study quality was assessed using the methods of Jadad and data were synthesized using a random effects model using weighted mean differences. In all, 33 trials reporting

48 treatment arms with 2165 patients were included. Phenylpropanolamine increased SBP 5.5 mmHg (95% CI: 3.1–8.0) and DBP 4.1 mmHg (95% CI: 2.2–6.0) with no effect on pulse. Patients with controlled hypertension were not at greater risk of blood pressure elevation. Immediate release preparations had greater effects on blood pressure than sustained release ones. Higher doses and shorter duration use also caused greater increases. Eighteen studies contained at least one treated subject having blood pressure elevations X140/90 mmHg, an increase in SBP X15 mmHg or an increase in DBP X10 mmHg. In conclusion, phenylpropanolamine caused a small, but significant increase in systolic blood pressure. The effect was more pronounced with shorter-term administration, higher doses of medication and immediate release formulations. Journal of Human Hypertension (2005) 19, 643–652. doi:10.1038/sj.jhh.1001869; published online 21 April 2005

Introduction

that medications containing phenylpropanolamine be voluntarily recalled over the concern of increased incidence of haemorrhagic stroke.5 However, other regulatory bodies such as the United Kingdom’s National Health Service’s Committee on Safety of Medicines have allowed phenylpropanolamine sales to continue, noting that the medication was mostly used for common cold remedies and at a lower maximum daily dose (100 mg) than that used in the United States (150 mg).6 The Committee did, however, caution physicians using phenylpropanolamine in patients with high blood pressure and heart disease. Given the high number of patients prescribed oral decongestants, we wished to evaluate the effect of oral phenylpropanolamine on pulse rate and blood pressure. We also wished to perform subgroup analysis to examine if the magnitude of changes on pulse rate and blood pressure were affected either by patient characteristics, such as age, sex or currently treated hypertension, or by drug characteristics such as extended or immediate release formulations and treatment duration.

Oral phenylpropanolamine is a common ingredient in many medications such as decongestants, cough remedies and weight control agents. There are numerous case reports in the literature suggesting that oral phenylpropanolamine can raise blood pressure to dangerous levels,1,2 while other reviews suggest that the danger from these medications is overexaggerated.3,4 In November 2000, The United States Food and Drug Administration recommended

Correspondence: Dr S Salerno, Department of Medicine (MCHKDM), Tripler Army Medical Center, 1 Jarrett White Road, Honolulu, HI 96859, USA. E-mail: [email protected] The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting those of the Department of the Army or the Department of Defense Received 3 January 2005; accepted 21 February 2005; published online 21 April 2005

Impact of phenylpropanolamine on blood pressure SM Salerno et al 644

Methods For this review, we searched MEDLINE (1966–2003) and Embase (1974–2003) for articles on adult patients using the text and keywords: sympathomimetic agents. An additional search using the MESH terms phenylpropanolamine was combined with the text words: hypertension, blood pressure, heart rate, adverse effects and clinical trial. We also searched the Cochrane library, searching the clinical trials registry for randomized trials, and the Cochrane Database of Systematic Reviews (DARE) for systematic reviews. All references of reviewed articles were scrutinized for additional articles missed by the computerized database search. All articles that were identified as randomized controlled trials in either the title or abstract were further screened by review of the full article. This was necessary since trials on the effectiveness of the preparations on weight loss or on cold symptoms often included extractable data on the effect of the preparations on vital signs without mentioning that fact in either the title or abstract. We screened articles based on the following criteria: randomization, placebo control, at least one group receiving a sympathomimetic medication, and extractable outcomes reported. Included study quality was assessed using a sixitem instrument developed and validated by Jadad et al.7 The six items in the Jadad scale include: description of randomization, adequacy of blinding, description of withdrawals and dropouts, appropriateness of statistical analysis, description of inclusion and exclusion criteria, and method for assessing adverse treatment effects. The Jadad study quality was assessed independently by two reviewers, with substantial inter-rater agreement (k: 0.84). Disagreements were arbitrated by consensus. Abstracted data included setting, country of origin, treatment characteristics (dose, duration, type of formulation, type of study) and demographics, number of participants enrolled, followup losses, adverse effects, and the outcomes of systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse. All outcomes were extracted as continuous variables. Analyses were performed using STATA (STATA 8.0, College Station, TX, USA). Assessment for publication bias was performed using the methods of Egger et al,8 heterogeneity was assessed visually with Galbraith plots as well as Q (w2) statistics using the methods of Mantel-Haenzel.9 The random effects model of DerSimonian and Laird10 was used to calculate summary weighted mean differences. Analysis of outcomes involved comparing weighted mean differences between control and treatment groups for all sympathomimetic drugs and several subgroups of studies. These subgroup analyses included probing for differences between extended and immediate release preparations of each drug, for short-term (o1 day) and long-term administrations of drugs, for low and high (4100 mg phenylpropa-

Journal of Human Hypertension

nolamine) doses of medications, for patients with and without hypertension, and for studies that did and did not include female patients. Further analyses were performed comparing if results differed between high- and low-quality (Jadad scores o6) studies and studies that specifically included baseline blood pressure readings immediately before administration of the treatment or placebo medication. Several measures of the sensitivity of the metaanalysis results to various assumptions were conducted. If publication bias was found, we calculated its potential impact using the ‘trim and fill’ method of Duval and Tweedie.11 We also explored several sources of heterogeneity, including year of publication, type of medication, inclusion of multiple genders, length of studies, study quality scores, and the type of sympathomimetic using metaregression.12

Results Selection of studies

A total of 380 studies were found in our search. In all, 347 articles were excluded. Studies were eliminated (Figure 1) that did not use oral phenylpropanolamine (n ¼ 94), were not randomized controlled trials (n ¼ 17), were not English language (n ¼ 13), were not human studies (n ¼ 7), were not adult studies (n ¼ 51), contained duplicate data to other published studies (n ¼ 4), used concomitant medication such as caffeine that could interfere with blood pressure (n ¼ 13), did not collect vital signs (n ¼ 136), and for other miscellaneous reasons (n ¼ 7). Five trials were excluded that reported collecting vital signs and included a mention in the text that there were ‘no differences,’ but provided no extractable data. Six of the articles were found with the hand review of article references. The final list of included articles contained 33 studies with 48 treatment arms.13–46 (Table 1).

380 Articles Reviewed

Reason for Exclusion

n=94

Not oral phenylpropanolamine

n=17

Not a randomized controlled Trial

n=13

Non English language

n=7

Animal study

n=51

Non adult study

n=4

Duplicate data

n=13

Included caffeine

n=136 No vital signs collected n=5

Vital signs listed as “no change”, no data given

n=7

Miscellaneous

33 Articles Included

Figure 1 Reasons for exclusion from meta-analysis.

Table 1 Characteristics of studies of phenylpropanolamine including blood pressure and pulse data Quality score (0–8)a

Study design Drug dose and type*

Alger13 (1993) United States Blackburn14 (1989) United States

Treatment of obesity Treatment of obesity and effect on blood pressure

Parallel

PPA (SR) 75 mg q.d.

18

100

37.5

No

8 weeks

4

A, B

Parallel

PPA (SR) 75 mg q.d. PPA (IR) 25 mg t.i.d.

881

63

33.1

No

1 day

5

A, F

Bradley15 (1989) United States

Treatment of obesity

Crossover

PPA (IR) 75 ng q.d.

12c

80

54.5 (25–67)

Yes

2 weeks

4

A, B

Broms46 (1982) Sweden

Treatment of perennial rhinitis

Crossover

20

52

33 (16–64)

Unknown

10 days

5

A, E

Dowse16 (1990) South Africa

Effect on blood pressure

Crossover

5

0

(20–24)

No

16 h

3

A,B,F

2 subjects with BP increases of 31/20 and 35/ 25 mmHg with the 100 mg dose

Goodman17 (1986) United States Graf18 (1999) Sweden

Effect on blood pressure Effect on nasal mucosa

Crossover

PPA (SR) 100 mg q.d. PPA (SR) 50 mg q.d. and BPA 12 mg q.d. PPA (IR) 25 mg (one dose) PPA (IR) 50 mg (one dose) PPA (IR) 100 mg (one dose) PPA (SR) 75 mg q.d.

18

0

25 (22–34)

No

7 days

6

A

Crossover

PPA (SR) 50 mg q.d.

15

47

(20–30)

No

8h

3

A, B, F

No report of magnitude of individual BP changes No report of magnitude of individual BP changes

Hendershot19 (2001) United States Horowitz21 (1979) Australia

Interaction with linezolid

42

Unknown

(18–45)

Unknown

9 days

6

A

No report of magnitude of individual BP changes

6

33

(22–24)

Unknown

1 day

5

A, F

Horowitz20 (1980) Australia


Parallel

PPA (IR) 85 mg (one dose) PPA (IR) 50 mg and 0.25 mg belladonna alkaloids

72

Unknown

(21–28)

No

1 day

6

A

Kroenke22 (1989) United States


Crossover

PPA (IR) 25 mg q 4 hours

26

46

57 (35–85)

Yes

2.5 days

6

A

Lake23 (1988) United States

Effect on sympathetic function Effect on blood pressure

Crossover

PPA (SR) 75 mg q.d.

14

17

23.7 (20–30)

No

2 weeks

4

A,C,F

2 subjects in treatment group had DBP 4110 mmHg Peak DBP4120 in 1 patient, 4110 mmHg in 4 patients, and 4100 mmHg in 7 patients with 85 mg PPA, peak DBP 4110 mmHg in 1 patient and 4100 mmHg in 3 patients on 50 mg PPA No report of magnitude of individual BP changes, peak treatment BP 161/ 106 compared to 159/109 placebo No mention of magnitude of individual BP changes

Crossover

PPA (SR) 150 mg (one dose) PPA (SR) 75 mg (one dose)

16

19

25 (19–36)

No

5h

6

A

22 mmHg DBP increase in 2 subjects DBP elevations of 20 mmHg reported in 7% of placebo and 11% in treatment groups No mention of magnitude of individual BP changes, all changes ‘clinically insignificant’ No report of magnitude of individual BP changes

Impact of phenylpropanolamine on blood pressure SM Salerno et al


Effect on blood Crossover pressure and pulse

PPA (SR) 100 mg q.d. PPA (IR) 60 mg q.d. 4 h 2 doses on two different days PPA (IR) 85 mg (one dose)

Quality Extreme hypertensive problemsb responses in treatment groups

One subject taking 150 mg PPA had BP 230/ 110 mmHg, 10 total subjects taking PPA with DBP4100 mmHg

645


Focus of study

Crossover

Patients

Female Mean age Patients with Trial length gender (%) (age range) hypertension included (years)

Study (year) country

646


Table 1 Continued Focus of study




Crossover

Lehtonen26 (1986) Sweden

Effect on stress urinary incontinence

Parallel

Liebson27 (1987) United States


Patients


Quality score (0–8)a

Quality problemsb

PPA (SR) 150 mg (one dose) PPA (SR) 75 mg (one dose) PPA (SR) 50 mg b.i.d.

16

19

25 (19–36)

No

5 hours

4

A, B

43

100

50 (33–79)

Unknown

14 days

8

Phase 1 Parallel Phase 2 Crossover

PPA (SR) 75 mg (one dose) PPA (IR) 25mg q 4 hours (three doses) PPA (SR) 75 mg (one dose)

150

42

No

12 h

5

A, E

59

47

25.9 (18–55) 25.9

McKenney28 (1991) United States Mitchell29 (1967) Australia


Crossover

PPA (SR) 75 mg q.d.

14

100

28.2 (20–40)

No

4 days

6

A


Crossover

PPA (SR) 50 mg b.i.d. and 0.25 mg of belladonna alkaloids

32

38

24.5 (19–53)

No

5 days

2

A, B, E, F

Noble30 (1988) United States Nuotto31 (1984) Finland

Effect on blood pressure Effect on psychological testing Effect on blood pressure in hypertensive patients on Bblockers

Parallel

PPA (SR) 75 mg (one dose) PPA (IR) 80mg (one dose, two study arms on separate occasions) PPA (IR) 25 mg (one dose)

144c

50

32.6

No

12 h

4

A, B

c

120

56

22

Unknown

90 minutes

3

A, B, C

7

0

36.3 (23–55)

Yes

6h

8

Pentel33 (1985) United States


Crossover

PPA (IR) 37.5 mg (one dose)

10

60

(18–35)

No

4h

5

A, F

Pentel34 (1988) United States

Effect on blood pressure with and without isometric exercise Effect on blood pressure

Crossover

PPA (IR) 37.5 mg (one dose)

6

0

(18–30)

No

2h

4

A, C, F

Crossover

PPA (SR) 75 mg and BPA 12 mg b.i.d. (3 doses)

13

85

48 (36–64)

Yes

1.5 days

5

A, F

O’Connell32 (1990) United States

Petrulis35 (1991) United States

Parallel Crossover

Extreme hypertensive responses in treatment groups Maximum SBP 230, DBP 160 mmHg, in treatment groups Maximum SBP 160 mmHg, DBP 110 mmHg in treatment group, SBP 170 mmHg, DBP 100 mmHg in placebo group One placebo patient had BP 176/116 mmHg , one PPA (SR) 75 mg patient had BP 164/116 mmHg , one PPA (IR) 25 mg t.i.d. patient had BP 154/ 110 mmHg One PPA patient had rise in SBP of 15 mmHg No increases listed by individual patient. No report of MAP in placebo or treatment group above 10 mmHg No report of magnitude of individual BP changes No report of magnitude of individual BP changes Maximum individual SBP increase 15 mmHg (treatment), 9 mmHg (placebo), DBP increase 16 mmHg (treatment), 9 mmHg (placebo) Maximum individual SBP increase 43 mmHg (treatment), 19 mmHg (placebo), DBP increase 37 mmHg (treatment), 23 mmHg (placebo) No report of magnitude of individual BP changes Proportion of BP4160/ 100 mmHg was 17% baseline, 13% treatment and 13% placebo



Table 1 Continued Quality score (0–8)a

Focus of study


Renvall36 (1979) Sweden

Treatment of allergic rhinitis

Parallel

PPA (SR) 50 mg b.i.d. PPA (SR) 100 mg b.i.d.

63

54

42 (15–78)

Unknown

4 days

5

A, E

Rushing38 (1997) United States Saltzman39 (1983) United States

Effect on energy expenditure Effect on blood pressure

Parallel

PPA (IR) 75 mg (one dose) PPA (IR) 25 mg t.i.d. PPA (SR) 75 mg q.d.

20

0

(18–29)

No

3h

4

A, E, F

14

0

27 (20–40)

No

4 days

3

A, B, F

Sands40 (1992) Korea

Crossover Effect on blood pressure in hypertensive patients on diuretics

PPA (IR) 25mg q.i.d.

20

60

62 (54–78)

Yes

2.5 days

6

A

Schteingart41 (1991) United States


Phase 1: PPA (SR) 75 mg q.d. Phase 2: PPA (SR) 75 mg q.d. PPA (IR) 25 mg (one dose)

101

84

No

6 weeks 12 weeks

6

A

36

Unknown

37.8 (21–61) Unknown

c

12

0

(22–42)

No

3h

5

A, F


PPA (IR) 0.33 mg/kg po (one dose) PPA (IR) 0.66 mg/kg po (one dose) PPA (SR) 75 mg q.d.

30

0

27.1

No

1 day

6

A


106

100

(18–44)

No

14 weeks

6

A

4

0

(24–26)

No

1 day

3

A, B, F

3 patients each in placebo and treatment group had SBP4150 mmHg , SBP increase 420, or DBP increase 410 mmHg. Maximum BP 154/ 92 mmHg 10 mmHg maximum increase in SBP and DBP reported in treatment group

42

Crossover

Parallel


Crossover

Effects on blood pressure during exercise

Crossover

Weintraub44 (1985) United States


Parallel

Zimmerman45 (1990) United States

Effect of urine pH on drug metabolism

Crossover

PPA (IR) 25 mg (one dose)

Quality problemsb

Extreme hypertensive responses in treatment groups No significant change in BP noted in individual patients No report of magnitude of individual BP changes One patient had 16 mmHg increase in DBP to 96 mmHg in PPA 25 mg t.i.d. group Maximum individual SBP increase 18 mm Hg (treatment), 24 mm Hg (placebo), DBP increase 16 mmHg (treatment), 12 mmHg (placebo) No report of magnitude of individual BP changes


Silverman (1980) United States Swain43 (1997) United States

Patients



BP ¼ blood pressure, SBP ¼ systolic blood pressure, DBP ¼ diastolic blood pressure, HR ¼ heart rate, PPA ¼ phenylpropanolamine, BPA ¼ brompheniramine, TER ¼ terfenadine, HCTZ ¼ hydrochlorothiazide, IR ¼ immediate release, SR ¼ slow release. Quality score of Jadad. b Quality Issues: A ¼ poor description of randomization technique, B ¼ lack of description of blinding and/or identical placebo, C ¼ failure to adequately describe withdrawals, D ¼ failure to describe statistical analysis, E ¼ no detailed inclusion and exclusion criteria, F ¼ failure to describe method of assessing adverse events. c More patients enrolled in study than listed — only patients included in study arms in analysis included. a

647



Study characteristics

There were 33 studies with 48 arms involving 2165 patients exposed to phenylpropanolamine. In all, 23 arms used immediate release formulations and 25 arms used sustained release. Studies originated in six different countries, with the majority (70%) coming from the United States. Of these, 22 trials were crossover trials, 10 used parallel groups and one used both design techniques. The 23 crossover trials averaged 5.5 washout days between treatments. The washout period ranged from 5 h to 14 days. The average study duration was 9.9 days, ranging from 1 to 140 days. Patients averaged 33.6711.15 years of age (range 16–85). Overall, 40% of patients were female, ranging from only men in 10 studies to only women in four. Five trials investigated the effect of sympathomimetic treatment among patients with stable, treated hypertension. The average Jadad quality score of included articles was 5.371.53 points. Effect on blood pressure and heart rate

Phenylpropanolamine (Figures 2–4) significantly increased systolic (5.5 mmHg; 95% CI: 3.1–8.0) and

diastolic (4.1 mmHg; 95% CI: 2.2–6.0) blood pressures with no effect on pulse (1.5 bpm; 95% CI: 3.0 to 0.06). Immediate release formulations had a slightly greater effect on both SBP and DBP than sustained release formulations (SBP: 5.9 vs 5.3 mm Hg; DBP: 6.1 vs 2.8 mmHg). Higher doses of phenylpropanolamine produced more effect than lower doses, while longer duration trials had less effect. Studies including female subjects did not differ substantially in impact on blood pressure than studies including men only. Five treatment arms among patients with known, stable, treated hypertension examined the effect of phenylpropanolamine. There was no statistically significant increase in average SBP, DBP or pulse rate (Table 2). There were no effects of age, country or year of study, study design or duration of washout period on our results. There was also no relationship between overall Jadad score and the effects. Several studies reported the baseline as well as posttreatment vital signs for both placebo and control groups. The results of analysis of this pre–post data were similar to the findings comparing the effects between placebo and treatment groups. Phenylpropanolamine had a greater effect compared with the placebo group (SBP: 6.1 vs 0.64 mmHg; DBP: 5.56

Study Alger (1993) Blackburn (1989) Blackburn (1989) Bradley (1989) Goodman (1986) Graf (1999) Graf (1999) Hendershot (2001) Kroenke (1989) Lake (1989) Lake (1991) Lake (1988) Lake (1989) Lake (1991) Lehtonen (1986) Liebson (1987) Liebson (1987) Liebson (1987) McKenney (1991) Noble (1988) Nuotto (1984) Nuotto (1984) O'Connel (1990) Pentel (1985) Pentel (1988) Petrulis (1991) Renvall (1979) Renvall (1979) Rushing (1997) Sands (1992) Schteingart (1992) Schteingart (1992) Silverman (1980) Weintraub (1986)

Weighted Mean Difference 5.53 (3.11,7.96)

Overall (95% CI)

-42.8

0 Systolic Blood Pressure (mmHg)

Figure 2 Impact of phenylpropanolamine on SBP. Journal of Human Hypertension

42.8


Study Alger (1993) Blackburn (1989) Blackburn (1989) Bradley (1989) Goodman (1986) Graf (1999) Graf (1999) Hendershot (2001) Horowitz (1980) Horowitz (1980) Kroenke (1989) Lake (1989) Lake (1991) Lake (1988) Lake (1989) Lake (1991) Lehtonen (1986) Liebson (1987) Liebson (1987) Liebson (1987) McKenney (1991) Noble (1988) Nuotto (1984) Nuotto (1984) O'Connel (1990) Pentel (1985) Pentel (1988) Petrulis (1991) Renvall (1979) Renvall (1979) Rushing (1997) Sands (1992) Schteingart (1992) Schteingart (1992) Silverman (1980) Weintraub (1986)

Overall (95% CI)

-22.5

Weighted Mean Difference 4.12 (2.22,6.01)

0 Diastolic Blood Pressure (mmHg)

22.5

Figure 3 Impact of phenylpropanolamine on DBP.

Study Alger (1993) Bradley (1989) Goodman (1986) Hendershot (2001) Kroenke (1989) Lake (1991) Lake (1989) Lake (1989) Lake (1991) Lake (1988) Liebson (1987) Liebson (1987) Mitchell (1968) Noble (1988) Nuotto (1984) Nuotto (1984) Pentel (1985) Sands (1992) Schteingart (1992) Schteingart (1992) Silverman (1980) Weintraub (1986)

Overall (95% CI)

-23.9

Weighted Mean Difference -1.46 (-2.99,-0.06)

0 Pulse (beats/minute)

23.9

Figure 4 Impact of phenylpropanolamine on pulse. Journal of Human Hypertension


Table 2 Post-treatment changesa in vital signs after phenylpropanolamine therapy SPB (mmHg) Phenylpropanolamine (n ¼ 48)b Studies with hypertensive patients (n ¼ 5) Studies with female subjects (n ¼ 33) Immediate release preparation (n ¼ 20) Slow release preparation ( n ¼ 26) Short term treatment (o1 day, n ¼ 28) High dose (4100 mg/day, n ¼ 7)

+5.53 +3.16 +5.42 +5.89 +5.26 +8.78 +9.46

(95% (95% (95% (95% (95% (95% (95%

CI CI CI CI CI CI CI

DBP (mmHg)

3.11–7.96) 2.23–8.55) 2.77–8.08) 2.41–9.36) 1.77–8.76) 5.82–1.73) 19.17–38.09)

+4.12 +2.16 +3.31 +6.05 +2.79 +6.99 +6.54

(95% (95% (95% (95% (95% (95% (95%


2.22–6.01) 0.98–5.31) 1.90–4.74) 2.69–9.41) 1.00–4.58) 4.55–9.44) 14.27–27.35)

Pulse (bpm) 1.46 +0.73 1.92 0.39 2.11 2.23 2.09

(95% (95% (95% (95% (95% (95% (95%


2.99–0.06) 1.14–2.61) 3.47–0.37) 3.04–2.26) 3.85–0.39) 3.62–0.34) 4.26–0.08)

a

Weighted mean difference in mean pooled placebo and active therapy subject vital signs at baseline compared with vital signs after treatment. Number of study arms analysed.

b

Table 3 Tests of heterogeneity and publication bias Outcome

Number of study arms

Heterogeneitya

Publication biasb

SBP DBP Heart rate

34 34 22

o0.001 o0.001 o0.001

0.208 0.588 0.060

a 2

w test; Po0.10 indicates heterogeneity of the effect size between studies. Egger test; Po0.10 indicates bias against small studies with negative findings. b

vs 0.02 mmHg). Phenylpropanolamine also continued to lower subject pulse significantly (5.12 bpm) compared to placebo. There was no evidence of publication bias for SBP or DBP (Table 3). Among the 2165 patients exposed to phenylpropanolamine, there were multiple reports of clinically significant hypertension, and no reports of adverse clinical outcomes. We defined clinically significant hypertension as an SBP of X140 mmHg, a DBP X90 mmHg, an increase in SBP X15 mmHg or an increase in DBP X10 mmHg. In all, 18 of 33 (54 %) studies reported patients with at least one blood pressure in this range involving a minimum of 42 patients in treatment groups and 13 in placebo groups. Precise numbers were difficult to calculate, as five studies only defined maximum or mean blood pressure elevations without specifically stating the number of individual patients affected.

Discussion Our meta-analysis demonstrates that phenylpropanolamine causes small but significant increases in SBP and DBP and a reduction in pulse. Despite the small average effect, there were at least 118 episodes of clinically significant hypertension among the 2165 patients. There appeared to be a dose–response relationship between the magnitude of the drug dose and the effect on the blood pressure with more substantial elevations noted at doses higher than the 100 mg maximum daily dose recommended for overthe-counter use in the United Kingdom. PhenylJournal of Human Hypertension

propanolamine did not cause any clinically significant adverse outcomes. However, a rare event, such as an idiosyncratic extreme reaction to a sympathomimetic agent, may not be seen with this small sample size. The failure of phenylpropanolamine to cause more substantial elevations in blood pressure in controlled hypertensive patients suggests that this group may not be at increased risk compared with the general population. One explanation hypothesized in an earlier review suggests that hypertensive and overweight patients may have a higher basal sympathetic tone producing a tighter intrinsic regulation of sympathetic response and a higher therapeutic index upon exposure to sympathomimetic drugs.4 Therefore, the modest impact of sympathomimetic agents on blood pressure and pulse may be manageable within the context of treated hypertension in most patients. Interestingly, while young, female patients were the focus of the 2000 voluntary recall of phenylpropanolamine in the United States for hemorrhagic stroke, in our review the cardiovascular effects of phenylpropanolamine in studies including women were not significantly different than those studies only including men. Several questions remain after our analysis. Why do some patients have exaggerated blood pressure elevations when most patients, on average, have modest increases in SBP and DBP? Although we found no serious adverse effects in these randomized trials, we did observe that multiple seemingly healthy patients had as much as a 35 mmHg increase in SBP when exposed to phenylpropanolamine. One theory is that these patients have a degree of underlying autonomic instability. A prior study noted exaggerated blood pressure responses (mean systolic increase: 32 mmHg) in 14 patients with autonomic failure and orthostatic hypertension.47 Another trial suggested that a pharmacodynamic difference in receptor concentration or sensitivity may be a factor after noting significant blood pressure variability in response to intravenous phenylpropanolamine in nonobese subjects without postural hypotension or autonomic impairment.48 Future research might examine subsets of population at risk for autonomic insufficiency such as


diabetics to see if exaggerated blood pressure responses to sympathomimetic agents are present. While few patients had extreme elevations in blood pressure, many individual patients had changes raising the blood pressure from low normal to high normal or slightly hypertensive levels. Given the paucity of adverse effects reported in our studies, it is unlikely these changes are of clinical significance to most healthy patients. Effects of sympathomimetic agents may be important when considered on a population basis given their widespread use as diet pills and decongestants. Our study had several limitations. First, the population studied included insufficient geriatric patients to reach conclusions on use in the elderly. Second, we only evaluated one element of safety — blood pressure and pulse. Sympathomimetic agents have many other potential adverse effects such as drug–drug interactions that are beyond the scope of this paper. Many of our included studies pooled baseline vital signs data for placebo and treatment groups. Separate analysis of studies with separate baseline data for both groups, as well as higher quality studies in general showed less pronounced effects on vital signs. Therefore, we may have overexaggerated the impact of sympathomimetic agents in our results. However, we felt it is important to highlight the worst-case scenario for patients and chose to include the lesser quality studies. Many studies reported average blood pressure and pulse responses rather than individual data. Average results may mask extreme responses. If 37 individuals had only a 1 or 2 point increase in SBP, but one subject increased their blood pressure by 30 points, this would yield an average response of only 1–2 points. The emergence of a risk of haemorrhagic stroke and marked blood pressure elevation in postmarketing surveillance with phenylpropanolamine was seen in only a handful of cases when the total number of doses among the general population was in the millions. Our data cannot be used to fully eliminate the possibility of this risk. Finally, our observations on female patients may have been affected by lack of sufficient studies entirely made up of female subjects. We conclude that phenylpropanolamine causes a small but significant mean increase in SBP and DBP while decreasing the heart rate. These effects are most substantial with high doses of medication and during short-term medication administration. Patients with stable controlled hypertension did not have an exaggerated hypertensive response. We found numerous episodes of increases in SBP and DBP from low normal to high normal values, and multiple episodes of extreme elevation of blood pressure. While we did not find any life-threatening adverse effects of blood pressure elevation, a metaanalysis cannot predict how any individual patient will react, especially since few studies included patients with high-risk medical conditions. Our

study supports the November 2000 conclusions of the United Kingdom’s Medicines and Healthcare Products Regulatory Agency Committee on the Safety of Medicines that supported continuing a maximum daily dose limit of 100 mg on phenyl propanolamine products and recommending caution in patients with high blood pressure and heart disease.

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