Angioedema in the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial ALLHAT

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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 Probstfield
• for the ALLHAT Collaborative Research Group
• Sponsored by the National Heart, Lung, and Blood
  Institute (NHLBI)
• The University of Texas School of Public Health
• Houston, Texas

www.allhat.org
J Clin Hypertens 20068649-656
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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.Patien
ts 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.
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ACE-Inhibitors Background

• Introduced in the early 1980s 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

Am J Hypertens 200417103-111
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Angioedema and ACE-Inhibitors ALLHAT vs.
OCTAVE
ALLHAT ACE-inhibitor arm
OCTAVE ACE-inhibitor arm

• 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)

JAMA 2002 2882981-2997
Am J Hypertens 200417103-111

Arch Int Med, in press (with permission)
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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
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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.
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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

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Antihypertensive Trial
1 with prior ACE-I use
1 with prior ACE-I use
Mean follow-up time 4.9 years for
chlorthalidone, amlodipine, and lisinopril
treatment groups 3.3 years for doxazosin
treatment group
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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

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Baseline Characteristics of Participants with
Angioedema
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.
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Baseline Characteristics of Participants with
Angioedema (2)
mg/dl, mean (SD) mEq/dl, mean (SD)
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Baseline Characteristics of Participants with
Angioedema Assigned to Step 1 Lisinopril vs.
Entire Step 1 Lisinopril Cohort
JAMA 2002 2882981-2997
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Race Distribution by Treatment Group of
Participants with Angioedema
6/8
2/3
23/37
3/5
13/37
2/5
1/3
2/8
1/37
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Time from Randomization to Onset of Angioedema
For participants with gt1 angioedema episode,
only the first is considered.
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Time from Most Recent Step 1 Dose Increase to
Onset of Angioedema
For participants with gt1 angioedema episode,
only the first is considered.
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Clinical Status of Participants Following
Angioedema
At time of angioedema report
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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 200417103-111
18
Angioedema and ACE-Inhibitors ALLHAT vs.
OCTAVE
ALLHAT ACE-inhibitor arm
OCTAVE ACE-inhibitor arm

• 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

JAMA 2002 2882981-2997
Am J Hypertens 200417103-111
19
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.