Angioedema in the Antihypertensive and Lipid-

Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)*

Linda Piller*, Charles Ford, Barry Davis, Chuke Nwachuku, Henry Black, Suzanne Oparil, Saib Gappy, Tamrat Retta,

Jeffrey Probstfieldfor the ALLHAT Collaborative Research Group

Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)

*The University of Texas School of Public HealthHouston, Texas

ALLHAT

www.allhat.org *J Clin Hypertens 2006;8:649-656

Abstract

ALLHAT, the largest antihypertensive study conducted to date, randomized 42,418 participants to one of four antihypertensive drug classes/drugs (diuretic/chlorthalidone, calcium-channel blocker/amlodipine, angiotensin-converting enzyme (ACE) inhibitor/lisinopril, and alpha-blocker/doxazosin), with 9054 participants assigned to lisinopril. This large patient sample, combined with the double-blind design of ALLHAT, provides a large and diverse population in which to further examine the occurrence of angioedema, a rare but potentially life-threatening side effect of ACE-inhibitors. The purpose of this presentation is to describe the characteristics, both within and between treatment groups, of treated hypertensive participants with angioedema.

Patients who developed angioedema during ALLHAT were compared for baseline characteristics and for the temporal relationship of changes in antihypertensive drug administration to the onset of angioedema. Results were as follows: Fifty-three ALLHAT participants developed angioedema during active follow-up in ALLHAT. Of these, 55% were black, 60% male, 70% were assigned to the ACE-inhibitor lisinopril (0.83 events per 1000 person-years), 15% to chlorthalidone (0.11 events per 1000 person-years), 9% to doxazosin (0.17 events per 1000 person-years), and 6% to amlodipine (0.07 events per 1000 person-years). Three cases (6%) occurred within a day of randomization, 22% within the first week, 34% within the first month, and 68% within the first year. In addition, 3 patients (6%) had a dose increase of their assigned medication within a week prior to onset, but over half (51%) had no prior dose increase. One patient died following the angioedema onset. The occurrence of angioedema cases in the ACE-inhibitor arm of ALLHAT corresponds with the previously reported association of angioedema and ACE-inhibitor use.

ALLHAT

ACE-Inhibitors: Background

• Introduced in the early 1980’s for treatment of refractory hypertension

• Side effects– Persistent, nonproductive cough (5-6% of patients)– Angioedema (0.1-0.7% of patients)

• 2-4 times more frequent in Black patients• Life-threatening if respiratory compromise• The OCTAVE (“Omapatrilat Cardiovascular Treatment vs.

Enalapril”) trial* reported the largest series of angioedema cases associated with ACE-inhibitor use, and ALLHAT reported the largest number of Black participants in which to study angioedema associated with ACE-inhibitors.

• Also associated with other etiologies, including aspirin, NSAID, penicillin, ARBs, and peanuts

ALLHAT

*Am J Hypertens 2004;17:103-111

Angioedema and ACE-Inhibitors: ALLHAT* vs. OCTAVE†

• 9054 assigned to lisinopril, including 3210 black participants (35%)

• Angioedema reported as a safety (serious adverse) event; no committee adjudication

• 37/9,054 (0.41%) reported angioedema (23/3,210 [0.72%] of Black participants)

• 12,634 assigned to enalapril, including 1247 black participants (10%)

• Angioedema reported as a study endpoint; all reports adjudicated by a committee blinded to RX

• 86/12,634 (0.68%) reported angioedema (20/1237 [1.62%] of Black participants)‡

ALLHAT ACE-inhibitor arm OCTAVE ACE-inhibitor arm

*JAMA 2002; 288:2981-2997 †Am J Hypertens 2004;17:103-111 ‡Arch Int Med, in press (with permission)

ALLHAT

African American Patients and ACE-Inhibitors: Background

• Prevalence, severity, and impact of hypertension are increased in African Americans.

• African American patients demonstrate decreased response to some monotherapy agents, including ACE-inhibitors, compared to CCBs and diuretics, in lowering blood pressure.

• Angioedema secondary to ACE-inhibitors occurs 2-4 times more often in African American patients than in other groups.

From JNC 7, 2003

ALLHAT

Rationale and Objective

With 42,418 participants, including 9,054 participants (3,210 black participants) assigned to the ACE-inhibitor lisinopril treatment group, ALLHAT provides the second largest series of patients in which to study ACE-inhibitor associated angioedema and the largest series in which to study ACE-inhibitor associated angioedema among Black participants.

This presentation will describe the characteristics of participants who developed angioedema while in ALLHAT.

ALLHAT

Antihypertensive Trial Design

• Randomized, double-blind, active-controlled clinical trial

• Purpose: To determine whether the occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic

• 42,418 high-risk hypertensive patients ≥ 55 years, from 623 clinical centers

• Conducted from February, 1994, through March, 2002

• Large, simple trial

ALLHAT

Antihypertensive Trial42,418 high-risk

hypertensive patients

Chlorthalidonen=15,255

Amlodipinen=9,048

Lisinopriln=9,054

Doxazosinn=9,061

8 patients (0.05%)with angioedema

3 patients (0.03%)with angioedema

37 patients(0.41%)with angioedema

5 patients (0.06%)with angioedema

6 White

2 Black

1 White

2 Black

13 White

23 Black

1 Asian/Pacific Islander

3 White

2 Back

ALLHAT

1 with priorACE-I use

1 with priorACE-I use

Mean follow-up time: 4.9 years for chlorthalidone, amlodipine, and lisinopril treatment groups; 3.3 years for doxazosin treatment group

Symptoms of Angioedema

• Swelling beneath the skin, subcutaneous tissues, and mucous membranes

• Typical involvement of face, lips, or glossopharyngeal areas– Involvement of larynx, glottis, or tongue can

produce airway obstruction– Respiratory compromise may be life-threatening

• Occasional involvement of hands, feet, or abdominal viscera

ALLHAT

Baseline Characteristics of Participants with Angioedema

Assigned (Step 1) Treatment Group

Chlor Amlod Lisin Doxaz

No. randomized 15,255 9,048 9,054 9,061

No. w/angioedema (% of rz) 8 (0.05) 3 (0.03) 37 (0.41) 5 (0.06)

Female, n (%) 5 (62.5) 0 13 (35) 3 (60)

Black, n (%) 2 (25) 2 (66.7) 23 (62) 2 (40)

BP treatment

Untreated at BL 2 (25) 0 3 (8) 0

Treated > 2 mos 6 (75) 3 (100) 34 (92) 5 (100)

Current/past smoker 6 (75) 2 (67) 27 (73) 4 (80)

*Baseline characteristics are given as number of participants with angioedema in a given treatment group and percentage of total participants with angioedema in that group.

ALLHAT

Baseline Characteristics of Participants with Angioedema (2)

Assigned (Step 1) Treatment Group

Chlor Amlod Lisin Doxaz

No. w/angioedema (% of rz) 8 (0.05) 3 (0.03) 37 (0.41) 5 (0.06)

Hx. of diabetes 1 (13) 0 4 (11) 1 (20)

Hx. aspirin use, n (%) 2 (25) 1 (33) 14 (38) 2 (40)

BMI, kg/m2, mean (SD) 29.0 (5.2) 31.7 (8.2) 29.4 (7.6) 29.0 (9.0)

Serum creatinine* 0.90 (0.14) 0.97 (0.06) 1.08 (0.33) 0.94 (0.15)

Serum potassium† 4.1 (0.44) 4.1 (0.50) 4.4 (1.93) 3.9 (0.48)

*mg/dl, mean (SD) †mEq/dl, mean (SD)

ALLHAT

Baseline Characteristics of Participants with Angioedema Assigned to Step 1

Lisinopril vs. Entire Step 1 Lisinopril Cohort

Step 1 Lisinopril Treatment Group

Participants with angioedema

(n=37)

Total cohort* (n=9054)

Age, mean (SD), years 66.59 (8.35) 66.9 (7.7)

Female, n (%) 13 (35.1) 4187 (46.2)

Black, n (%) 23 (62.16) 3210 (35.5)

BP treatment at baseline, n (%) 34 (91.9) 8164 (90.2)

Current smoker, n (%) 14 (37.8) 1981 (21.9)

Hx. of diabetes, n (%) 4 (10.8) 3212 (35.5)

Hx. of CHD, n (%) 10 (27.0) 2270 (25.3)

Fasting glucose, mean (SD), mg/dl 106.68 (28.72) 122.9 (56.1)

Serum potassium, mean (SD) mg/dl 4.4 (1.93) 4.4 (0.70)

Aspirin use 14 (37.8) 3258 (36.0)

ALLHAT

*JAMA 2002; 288:2981-2997

Race Distribution by Treatment Group of Participants with

Angioedema

0%

20%

40%

60%

80%

100%

Chlor n=8

Amlod n=3

Lisin n=37

Doxaz n=5%

of

an

gio

ed

em

a p

art

icip

an

ts in

tr

ea

tme

nt

gro

up

White Black Asian/Pacific

6/8

2/81/3

2/3

13/37

23/37

1/37

3/5

2/5

ALLHAT

Time from Randomization to Onset of Angioedema*

Number of Patients (%)

Chlorthalidone Amlodipine Lisinopril Doxazosin

Within 1 week 2 (25%) 0 8 (22%) 2 (40%)

Within 1 month 2 (25%) 0 13 (35%) 3 (60%)

Within 1 year 2 (25%) 3 (100%) 27 (73%) 5 (100%)

1 year incidence 0.01% 0.03% 0.30% 0.06%

> 1 year 6 (75%) 0 10 (27%) 0

Total w/angioedema (% of randomized)

8 (0.05%) 3 (0.03%) 37 (0.41%) 5 (0.06%)

Total randomized 15,255 9,048 9,054 9,061

*For participants with >1 angioedema episode, only the first is considered.

ALLHAT

Time from Most Recent Step 1 Dose Increase to Onset of

Angioedema*Number of Patients

Chlorthalidone Amlodipine Lisinopril Doxazosin

Within 1 week 0 1 2 0

Within 1 month 0 2 6 1

Within 1 year 2 3 12 2

> 1 year 2 0 5 0

Total with dose increase

4 (50%) 3 (100%) 17 (46%) 2 (20%)

No dose increase 4 (50%) 0 20 (54%) 3 (60%)

*For participants with >1 angioedema episode, only the first is considered.

ALLHAT

Clinical Status of Participants Following Angioedema*

Number of Patients (%)

Chlorthalidone Amlodipine Lisinopril Doxazosin

Recovered 6 (75%) 3 (100%) 32 (87%) 5 (100%)

Alive with sequelae 1 (13%) 0 0 0

Under treatment for sequelae

1 (13%) 0 4 (11%) 0

Death 0 0 1 (3%) 0

Total w/angioedema 8 3 37 5

*At time of angioedema report

ALLHAT

Although ALLHAT provided the largest series of patients in which to study ACE-I associated angioedema, the OCTAVE (“Omapatrilat Cardiovascular Treatment vs. Enalapril”) trial* reported the largest series of angioedema cases associated with ACE-inhibitor use.

*Am J Hypertens 2004;17:103-111

ALLHAT

Angioedema and ACE-Inhibitors: ALLHAT* vs. OCTAVE†

• 9054 assigned to lisinopril, including 3210 black participants (35%)

• Angioedema reported as a safety (serious adverse) event; no committee adjudication

• 37/9,054 (0.41%) reported angioedema (23/3,210 [0.72%] black participants)

• 12,634 assigned to enalapril, including 1247 black participants (10%)

• Angioedema reported as a study endpoint; all reports adjudicated by a committee blinded to RX

• 86/12,634 (0.68%) reported angioedema

ALLHAT ACE-inhibitor arm OCTAVE ACE-inhibitor arm

*JAMA 2002; 288:2981-2997 †Am J Hypertens 2004;17:103-111

ALLHAT

Conclusions

• ALLHAT confirms the previously reported increased risk of ACE-inhibitor associated angioedema in Black patients.

• Angioedema is a measurable risk of ACE-inhibitor treatment, and treating physicians should be especially vigilant for even the mildest signs and symptoms.

• Recognition of angioedema is imperative and necessitates immediate and permanent discontinuation of ACE-inhibitors.

ALLHAT